Triazole phenyl compounds as agonists of the APJ receptor

ABSTRACT

Compounds of Formula I and Formula II, pharmaceutically acceptable salt thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: (I), (II) where the definitions of the variables are provided herein.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/422,875, filed on Nov. 16, 2016, which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.

FIELD OF THE INVENTION

The present invention relates to compounds capable of acting as agonists of the APJ Receptor, and compositions that include compounds that are agonists of the APJ Receptor. The compounds and compositions may be used to activate the APJ Receptor and to treat various disease conditions. An example of one area where such compounds may be used is in the treatment of cardiovascular conditions. In particular, the compounds may be used to improve contractility and ejection fraction in subjects with chronic heart failure and may be used to treat patients with heart failure with reduced ejection fraction and patients with heart failure with preserved ejection fraction.

BACKGROUND OF THE INVENTION

Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptor like-1). The APJ receptor is a member of the rhodopsin-like G protein-coupled receptor (GPCR) family. The apelin/APJ system has been observed in many tissues such as heart, kidney, pancreas, lung and the central nervous system. This suggests diverse roles of the system in the physiology and pathology of mammals.

Apelin peptides are processed from a 77 residue pre-pro form into smaller bioactive fragments, mainly a 36 residue form (Apelin 42-77—also referred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin 65-77—also referred to as Apelin-13) Hosoya et al., J. Biol. Chem. 275:21061-21067, 2000. Apelin peptides were previously determined to be endogenous ligands for the orphan APJ receptor, a member of the seven transmembrane G-protein-coupled receptor superfamily. Tatemoto et al., Biochem. Biophysi. Res. Commun. 251:471-476, 1998. One of the shorter more active isoforms identified, pyroglutamated apelin-13 ([PE65]Apelin-13 (65-77), has been reported to be the most potent and abundant form of apelin in cardiac tissue. Maguire et al., Hypertension 54:598-604, 2009. In vitro and preclinical models have suggested that the apelin/APJ system has a role in cardiovascular homeostasis as well as metabolism. Barnes et al., Heart 96:1011-1016, 2010. Circulating apelin levels are transient and Apelin-13 has a brief plasma half-life of <5 min leading to short-lived cardiovascular effects.

In vitro, exogenous apelin increases contractility at subnanomolar concentrations in atrial strips and whole rat hearts, and increases sarcomere shortening by up to 140% in isolated cardiomyocyctes. Barnes et al., Heart 96:1011-1016, 2010. Apelin also has a potent inotropic effect in an ex vivo isolated heart assay. In vivo, acute apelin infusion restores ejection fraction, increases cardiac output and reduces left ventricular end-diastolic pressure in rats with chronic heart failure. Berry et al., Circulation 110:187-193, 2004. Exogenous apelin potently enhances myocardial contractility without inducing left ventricular hypertrophy concomitant with reduction in ventricular preload and afterload. Barnes et al., Heart 96:1011-1016, 2010.

Studies from Kawamata et al and Hosoya et al have shown that that shorter peptide apelin-13 had approximately a 3.5-fold higher in vitro affinity to the APJ receptor than apelin-36. Kawamata et al., BBA 1538: 162-171, 2001, Hosoya et al., JBC 275: 21061-21067. Apelin-13 analogues were reported having a single substitution with either canonical or non-canonical amino acids. The authors also reported double and triple substitutions in apelin 66-77 and apelin 63-77, but not in apelin-13. The emphasis was on peptides reported to have higher in vitro affinity and potency than apelin-13. Nishizawa et al., in: T. Shioiri (ed.), Peptide Science 2000: Proceedings of the 37^(th) Japanese Peptide Symposium, pp. 151-154. Several if not all of these modified peptides are reported in later studies. U.S. Pat. No. 7,635,751.

In a 2003 study (Medhurst et al., J. Neurochemistry 84:1162-1172, 2003) in vitro activity of apelin-36, apelin-17 and apelin-13 was compared. It was concluded that all three peptides were approximately equipotent. C-terminal amidation resulted in about a 14-fold decrease in affinity. A more recent study (Hamada et al., J. Mol. Med. 22:547-552, 2008) reported cyclic analogues of apelin-13. When tested for in vitro activity all three analogues maintained function activity, although with reduced potency relative to apelin-13.

A shortened 12 amino acid-apelin peptide having ligand activity on APJ was reported in a 2009 patent (U.S. Pat. No. 7,635,751). The peptide could have a substitution of one non-canonical amino acid. In another application, WO 2013/111110 A2 and U.S. Pat. No. 8,673,848, cyclic mimetics of apelin have also been reported.

Another study reported synthesizing analogs of apelin-13 with amino acid substitutions with non-canonical amino acids at the C-terminal end of the molecule, but no pegylation at the N- or C-terminus or another site specific location. The use of internal PEG spacers (short PEG (n=4 or 6), however, was also reported in lower activity peptide analogs with deletions in the middle of the sequence that contained fewer amino acid residues than apelin-13. Murza et al. ChemMedChem 7:318-325, 2012. Additionally, PCT/US2013/075773 describes a group of modifications, including substitution of non-canonical amino acids and changes at the N- and C-terminal of the apelin molecule that can affect, inter alia, the potency of the molecule. The increased potency can be a result of increased half-life or decreased degradation relative to wild-type apelin.

Despite the advancements that have been made with respect to peptides, a need exists for small molecule agonists of the APJ receptor. However, some progress has been made in this area. For example, WO 2014/044738 discloses various benzimidazole-carboxylic acid amide derivatives as modulators of the APJ Receptor. Other small molecule agonists of the APJ receptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336, WO 2016/187308, WO 2015/184011, and WO 2015/188073.

A need continues to exist for agonists of the APJ receptor that may be used to treat various cardiovascular and other conditions. The present application discloses such agonists of the APJ receptor s that may be suitable for use as therapeutic agents in treating a variety of conditions. These compounds may find particular benefit in treating cardiovascular conditions. For example, such compounds may be beneficial in treating conditions such as chronic systolic heart failure and chronic diastolic heart failure.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein:

R¹ is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents; and further wherein two R^(1a) substituents on adjacent carbon atoms of the phenyl R¹ group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1a′) substituent and may include an oxo substituent if the ring is not an aromatic ring;

R^(1a′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R² is selected from —H, or C₁-C₄ alkyl or is absent in the compounds of Formula II;

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a) substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula —(C₃-C₈ cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h) substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈ cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R^(3h) substituents;

R^(3a) in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—Si(C₁-C₆ alkyl)₃, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with 1 or 2 oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents, and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO₂ moiety, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl).

Numerous other embodiments of the compound of Formula I and Formula II are set forth herein.

Also provided are pharmaceutical compositions that include at least one pharmaceutically acceptable excipient, carrier or diluent and the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments.

In other embodiments, the invention provides a method of treating a cardiovascular condition. Such methods typically include administering to a subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In some such embodiments, the cardiovascular condition is heart failure. In some such embodiments, the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. Thus, in some embodiments, the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure. In other embodiments, the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

In still other embodiments, the invention provides a method of improving cardiac contractility in a subject. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.

In still other embodiments, the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In such embodiments, the ejection fraction is increased in the subject after administration.

In still other embodiments, the invention provides a method of treating a condition in a subject where it is desired to activate the APJ Receptor. Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments. In some such embodiments, the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy or chronic kidney disease.

In other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for use in treating a cardiovascular condition. In some such embodiments, the cardiovascular condition is heart failure. In some such embodiments, the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. Thus, in some embodiments, the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure. In other embodiments, the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the cardiac contractility in a subject suffering from a cardiovascular condition.

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the ejection fraction in a subject suffering from a cardiovascular condition.

In still other embodiments, the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for treating a condition in a subject where it is desired to activate the APJ Receptor. In some such embodiments, the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy.

Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyr apelin-13 added to the human APJ-AT1R (angiotensin Type 1) double stable CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. Addition of pyr apelin-13 induces the positive cooperativity on the AT1R upon activation by APJ receptor.

FIG. 2 is a graph plotting different concentrations of angiotensin (AngIIl) with fixed concentration of pyr apelin-13 added to the human APJ receptor expressed in the CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. There was no positive cooperativity observed upon treatment with pyr apelin-13 when the human APJ receptor is expressed alone.

FIG. 3 is a graph plotting different concentrations of angiotensin (AngII) with fixed concentration of pyr apelin-13 added to the human AT 1R receptor expressed in the CHO cell line. The function of the inositol phosphate accumulation (IP1) was measured by Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm respectively. There was no positive cooperativity observed when the human AT1R receptor is expressed alone by pyr apelin-13 in the absence of APJ expression.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

The term “comprising” is meant to be open ended, i.e., all encompassing and non-limiting. It may be used herein synonymously with “having” or “including”. Comprising is intended to include each and every indicated or recited component or element(s) while not excluding any other components or elements. For example, if a composition is said to comprise A and B. This means that the composition has A and B in it, but may also include C or even C, D, E, and other additional components.

Certain compounds of the invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention. For example, when R⁴ is a phenyl group and is substituted with two groups bonded to the C atoms adjacent to the point of attachment to the N atom of the triazole, then rotation of the phenyl may be restricted. In some instances, the barrier of rotation is high enough that the different atropisomers may be separated and isolated.

As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.

As described above, this invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

As known by those skilled in the art, certain compounds of the invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula.

As noted above, compounds of the invention may exist in multiple tautomeric forms. This is particularly true in compounds of Formula I where R² is H. These forms are illustrated below as Tautomer A and Tautomer B:

Compounds of the invention are depicted structurally and named as compounds in the “Tautomer A” form. However, it is specifically contemplated and known that the compounds exist in “Tautomer B” form and thus compounds in “Tautomer B” form are expressly considered to be part of the invention. For this reason, the claims refer to compounds of Formula I and Formula II. Depending on the compound, some compounds may exist primarily in one form more than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as mixtures at room temperature whereas others may be isolated in one tautomeric form or the other. Examples of other tautomers associated with compounds of the invention are those with a pyridone group (a pyridinyl) for which hydroxypyridine is a tautomer and compounds with a ketone group with the enol tautomer. Examples of these are shown below.

Compounds of the present disclosure include, but are not limited to, compounds of Formula I and Formula II and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term “compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. In some embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C₁-C₄)alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers.

The term “solvate” refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.

The compounds of the invention may also contain naturally occurring or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T).

“Alkyl” refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises 1 to 20 carbon atoms. In some embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a (C₁-C₆)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (C₁-C₄)alkyl. This nomenclature may also be used for alkyl groups with differing numbers of carbon atoms. The term “alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom. For example, a group —O—(C₁-C₆ alkyl)-OH will be recognized as a group where an —O atom is bonded to a C₁-C₆ alkyl group and one of the H atoms bonded to a C atom of the C₁-C₆ alkyl group is replaced with a bond to the O atom of an —OH group. As another example, a group —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl) will be recognized as a group where an —O atom is bonded to a first C₁-C₆ alkyl group and one of the H atoms bonded to a C atom of the first C₁-C₆ alkyl group is replaced with a bond to a second O atom that is bonded to a second C₁-C₆ alkyl group.

“Alkenyl” refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E-form (cis or trans) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C₂-C₆)alkenyl group.

“Alkynyl” refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkynyl group.

“Alkoxy” refers to a radical —OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as —O—(C₁-C₆) alkyl or as —O—(C₁-C₆ alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as —O—(C₁-C₄) alkyl or as —O—(C₁-C₄ alkyl) groups group.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene. Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene. Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C₆-C₁₀ aryl groups. Aryl, however, does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.

“Carbonyl” refers to the radical —C(O) which may also be referred to as —C(═O) group.

“Carboxy” refers to the radical —C(O)OH which may also be referred to as —C(═O)OH.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 3 to 8 ring members may be referred to as a (C₃-C₈)cycloalkyl, a cycloalkyl group having 3 to 7 ring members may be referred to as a (C₃-C₇)cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C₄-C₇)cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C₃-C₁₀)cycloalkyl, a (C₃-C₈)cycloalkyl, a (C₃-C₇)cycloalkyl, a (C₃-C₆)cycloalkyl, or a (C₄-C₇)cycloalkyl group and these may be referred to as C₃-C₁₀ cycloalkyl, C₃-C₈ cycloalkyl, C₃-C₇ cycloalkyl, C₃-C₆ cycloalkyl, or C₄-C₇ cycloalkyl groups using alternative language.

“Heterocyclyl” refers to a cyclic group that includes at least one saturated, partially unsaturated, but non-aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include, 0, S and N and are independently chosen. Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems. Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms. The point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6-membered ring.

In some embodiments, a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Heterocyclyl groups may be fully saturated, but may also include one or more double bonds. Examples of such heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl, 2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2-dihydroazetenyl, and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo (═O) or oxide (—O—) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-only, 3,4-dihydroisoquinolin-1(2H)-only, indolin-only, 1H-imidazo[4,5-c]pyridin-2(3H)-only, 7H-purin-8(9H)-only, imidazolidin-2-only, 1H-imidazol-2(3H)-only, 1,1-dioxo-1-thiomorpholinyl, and the like.

“Disease” refers to any disease, disorder, condition, symptom, or indication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). Representative “haloalkyl” groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. The term “perhaloalkyl” means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom. For example, the term “perhaloalkyl”, includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

“Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound or salt of the present invention to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.

“Stereoisomer” refers to an isomer that differs in the arrangement of the constituent atoms in space. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As those skilled in the art will recognize. this amount is typically not limited to a single dose, but may comprise multiple dosages over a significant period of time as required to bring about a therapeutic or prophylactic response in the subject. Thus, a “therapeutically effective amount” is not limited to the amount in a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care provider. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder. “Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.

Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

EMBODIMENTS

The embodiments listed below are presented in numbered form for convenience and in ease and clarity of reference in referring back to multiple embodiments.

In a first embodiment, the invention provides a compound of Formula I or Formula II:

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein:

R¹ is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents; and further wherein two R^(1a) substituents on adjacent carbon atoms of the phenyl R¹ group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1a′) substituent and may include an oxo substituent if the ring is not an aromatic ring;

R^(1a′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R² is selected from —H, or C₁-C₄ alkyl or is absent in the compounds of Formula II;

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a) substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula —(C₃-C₈ cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h) substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈ cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R^(3h) substituents; R^(3a) in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₈ alkyl), —O—Si(C₁-C₆ alkyl)₃, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₈ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with 1 or 2 oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents, and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl

R^(4a) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO₂ moiety, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl).

2. The compound of embodiment 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[d]thiazolyl, 2H-indazolyl, quinoxalinyl, quinolinyl, or isoquinolinyl, any of which may unsubstituted or substituted with 1, 2, or 3 independently selected R^(1a′) substituents.

3. The compound of embodiment 1 or embodiment 2 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

4. The compound of embodiment 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R^(1a) substituents, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents.

5. The compound of embodiment 1 or embodiment 4 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, or —S(═O)₂N(C₁-C₆ alkyl)₂.

6. The compound of embodiment 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

when drawn across a bond, indicates the point of attachment to the rest of the molecule.

7. The compound of any one of embodiments 1-6 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R² is —H or is absent in the compounds of Formula II.

8. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridinyl, or pyrimidinyl, any of which may be unsubstituted or substituted with 1, 2, 3, or 4 R^(4a) substituents.

9. The compound of any one of embodiments 1-8 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(4a) is in each instance independently selected from —F, —Br, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl.

10. The compound of embodiment 9 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(4a) is in each instance independently selected from —F, —CF₃, or —OCH₃.

11. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a monocyclic or bicyclic C₆-C₁₀ aryl group that is unsubstituted or is substituted with 1, 2, or 3 R^(4a) substituents.

12. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the heteroaryl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4a) substituents.

13. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a monocyclic 3-6 membered cycloalkyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(4a) substituents.

14. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a straight or branched chain C₁-C₆ alkyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents.

15. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

16. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

17. The compound of any one of embodiments 1-7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridyl, or pyrimidinyl substituted with 1 or 2 R^(4a) substituents.

18. The compound of embodiment 17 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the R^(4a) substituents are —O—(C₁-C₂ alkyl) groups.

19. The compound of embodiment 17 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

20. The compound of embodiment 17 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

21. The compound of embodiment 17 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

22. The compound of any one of embodiments 1-21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyrazine-1-oxide, pyradizinyl, pyridinyl, phenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, piperidin-2-onyl, tetrahydropyrimidin-2(1H)-onyl, 1,3-oxazinan-2-onyl, pyrrolidin-2-onyl, pyrrolidinyl, cyclopentyl, cyclohexyl, benzimidazolyl, isoindolinonyl, 1H-imidazo[4,5-c]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, or 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, any of which may be unsubstituted or substituted with 1 or 2 R^(Q) substituents.

23. The compound of embodiment 22 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyridinyl, or phenyl any of which may be unsubstituted or substituted with 1 or 2 R^(Q) substituents.

24. The compound of embodiment 22 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R^(Q) substituents.

25. The compound of any one of embodiments 1-21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S and Q is unsubstituted or is substituted with 1 or 2 R^(Q) substituents.

26. The compound of embodiment 25 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is a pyrimidinyl pyridinyl, or pyrazinyl group and Q is unsubstituted or is substituted with 1 or 2 R^(Q) substituents.

27. The compound of any one of embodiments 1-26 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(Q) in each instance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —S(═O)₂—(C₁-C₆ alkyl.

28. The compound of any one of embodiments 1-26 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(Q) in each instance is independently selected from —F, —Cl, —Br, —CN, or —CH₃.

29. The compound of any one of embodiments 1-21 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

30. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

31. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing or the mixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the rest of the molecule.

32. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

33. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

34. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautoimer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing or the mixture thereof, wherein Q is

wherein the symbol

when drawn across a bond, indicates the point of attachment to the rest of the molecule.

35. The compound of embodiment 29 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

36. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R³⁹)-Q, a group of formula -(heterocyclyl)-Q, or -Q.

37. The compound of embodiment 36 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q.

38. The compound of embodiment 37 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q and further wherein,

R^(3d) and R^(3e) are independently selected from —H, or —C₁-C₆ alkyl; and

R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH, or —O—(C₁-C₆ alkyl).

39. The compound of embodiment 36 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is a group of formula -(heterocyclyl)-Q.

40. The compound of embodiment 39 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein the heterocyclyl of the -(heterocyclyl)-Q R³ group is a piperidinyl that is unsubstituted or is substituted with 1 or 2 R^(3h) substituent.

41. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

42. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

43. The compound of any one of embodiments 1-35 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

44. The compound of embodiment 1, wherein the compound is selected from

-   (1R,2S)—N-(5-(3-bromophenyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-cyanophenyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-chlorophenyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; -   (2R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; -   (2R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; -   2-(2-cyano-4-fluorophenyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   (2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; -   2-(2-cyano-4-fluorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1S,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   2-(4-chlorophenyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (3S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; -   (3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; -   (1R,2S)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (3S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; -   (3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; -   (3S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-3-piperidinesulfonamide; -   (3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-3-piperidinesulfonamide; -   (3S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-piperidinesulfonamide; -   (3R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-piperidinesulfonamide; -   (2S,3R)—N-(4-((1r,2R,6S)-2,6-dimethoxycyclohexyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (3R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-piperidinesulfonamide; -   (3S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-piperidinesulfonamide; -   2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   (1R,2S)—N-(5-(2,2-difluoro-1,3-benzodioxol-5-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (1R,2S)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propane     sulfonamide; -   (1S,2S)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (1R,2S)-1-((tert-butyl(dimethyl)silyl)oxy)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propane     sulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)-3-(5-cyano-2-pyrimidinyl)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (2S,3R)—N-(5-(3-cyanophenyl)-4-(4,6-dimethoxy-5-pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   2-(4-chlorophenyl)-N-(5-phenyl-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide; -   (2S,3R)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; -   (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; -   (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide; -   (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide; -   5-bromo-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-pyridinesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1S,2S)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-N-(5-phenyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (3R,5S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide; -   (1R,2S)—N-(5-(4-tert-butylphenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(1,3-benzodioxol-5-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3,4-dichlorophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(2,4-dichlorophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3,4-difluorophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   3-(4-(2,6-dimethoxyphenyl)-5-((((1S,2R)-2-methoxy-1-methyl-2-(5-methyl-2-pyrimidinyl)ethyl)sulfonyl)amino)-4H-1,2,4-triazol-3-yl)-N,N-dimethylbenzenesulfonamide; -   (1R,2S)—N-(5-(2-amino-1,3-benzothiazol-6-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-cyano-4-methoxyphenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(4-methylphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(2,5-dimethoxyphenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(2,3-dihydro-1-benzofuran-5-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-bromophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(4-phenoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(4-(diethylamino)phenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-quinoxalinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-cyanophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-chlorophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propane     sulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propane     sulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-quinolinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-methyl-2H-indazol-7-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(2-methyl-2H-indazol-7-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-methyl-2H-indazol-7-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-methyl-2H-indazol-7-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-isoquinolinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclopropyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-methylcyclopropyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1S,2S)—N-(4-(1-methylcyclopropyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;     or -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-phenyl-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide;     or     the pharmaceutically acceptable salt thereof, the tautomer thereof,     the pharmaceutically acceptable salt of the tautomer, the     stereoisomer of any of the foregoing, or the mixture thereof.

45. The compound of embodiment 1, wherein the compound is selected from

-   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (3S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide; -   (1R,2S)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1S,2S)—N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(4-methylphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-cyanophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; -   (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1S,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide; -   (1R,2S)—N-(5-(1,3-benzodioxol-5-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-bromophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; -   (1R,2S)—N-(5-(3-chlorophenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;     or -   (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide;     or     the pharmaceutically acceptable salt thereof, the tautomer thereof,     the pharmaceutically acceptable salt of the tautomer, the     stereoisomer of any of the foregoing, or the mixture thereof.

46. The compound of embodiment 1, wherein the compound is selected from

-   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclopropyl)-5-(2-methyl-2H-indazol-4-yl)-4H-1,2,4-triazol-3-yl)-2-propane     sulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(2-methyl-2H-indazol-4-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(2-methyl-2H-indazol-4-yl)-4-(2-propanyl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclobutyl)-5-(2-methyl-2H-indazazol-4-yl)-4H-1,2,4-triazol-3-yl)-2-propane     sulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(2-methoxyphenyl)-4-((3R)-tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-(3-methoxyphenyl)-4-((3S)-tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (2S,3R)—N-(5-(2-methyl-2H-indazol-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(3-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-(3-(difluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; -   (1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide; -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-((2R)-1-methoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide; -   (1S,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-propanyloxy)-2-propanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-((2S)-1-methoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)-3-(5-chloro-2-pyridinyl)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide; -   (2S,3R)—N-(5-(2-bromophenyl)-4-(2,2-dimethyl-1,3-dioxan-5-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanesulfonamide;     or -   (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(2-methoxyethyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide;     or the pharmaceutically acceptable salt thereof, the tautomer     thereof, the pharmaceutically acceptable salt of the tautomer, the     stereoisomer of any of the foregoing, or the mixture thereof. In     some embodiments, the invention provides one of the compounds listed     above or the pharmaceutically acceptable salt thereof, or the     mixture thereof.

47. The compound of embodiment 1, wherein the compound has the formula IA

or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein:

R¹ is as defined in embodiment 1;

X is selected from CH or N;

Z is selected from CH or N;

R^(3d) and R^(3e) are independently selected from —H or —C₁-C₃ alkyl;

R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH, or —O—(C₁-C₆ alkyl);

Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1 or 2 R^(Q) substituent; and

R^(Q) is independently selected from —F, —Cl, —Br, —CN, or —C₁-C₆ alkyl.

48. The compound of embodiment 47 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein:

X is CH;

Z is CH;

R^(3d) and R^(3e) are independently selected from —H or —CH₃;

R^(3f) and R^(3g) are independently selected from —H, —CH₃, —OH, —OCH₃, or —OCH(CH₃)₂;

Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1 or 2 R^(Q) substituent; and R^(Q) is independently selected from —F, —Cl, —Br, —CN, or —CH₃.

49. The compound of embodiment 47 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein:

X is N;

Z is N;

R^(3d) and R^(3e) are independently selected from —H or —CH₃;

R^(3f) and R^(3g) are independently selected from —H, —CH₃, —OH, —OCH₃, or —OCH(CH₃)₂;

Q is a phenyl, a pyrimidinyl, a pyridinyl, or a pyrazinyl any of which are unsubstituted or are substituted with 1 or 2 R^(Q) substituent; and

R^(Q) is independently selected from —F, —Cl, —Br, —CN, or —CH₃.

50. The compound of any one of embodiments 47-49 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[d]thiazolyl, 2H-indazolyl, quinoxalinyl, quinolinyl, or isoquinolinyl, any of which may unsubstituted or substituted with 1, 2, or 3 independently selected R^(1a′) substituents.

51. The compound of any one of embodiments 47-49 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

52. The compound of any one of embodiments 47-49 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R^(1a) substituents, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents.

53. The compound of any one of embodiments 47-49 or 52 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, or —S(═O)₂N(C₁-C₆ alkyl)₂.

54. The compound of any one of embodiments 47-49 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.

55. In another embodiment, the invention provides a pharmaceutical composition, comprising the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, and at least one pharmaceutically acceptable excipient.

56. A pharmaceutical composition, comprising the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

57. A pharmaceutical composition, comprising the compound of any one of embodiments 1-54 and at least one pharmaceutically acceptable excipient.

58. A pharmaceutical composition, comprising the pharmaceutically acceptable salt of the compound of any one of embodiments 1-54 and at least one pharmaceutically acceptable excipient.

59. The pharmaceutical composition of embodiment 55, further comprising a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

60. The pharmaceutical composition of embodiment 55, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

61. In another embodiment, the invention provides a method of treating a cardiovascular condition, the method comprising: administering to a subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-60.

62. The method of embodiment 61, wherein the cardiovascular condition is heart failure.

63. The method of embodiment 61, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

64. The method of embodiment 61, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

65. The method of embodiment 61, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

66. The method of embodiment 61, wherein the cardiovascular condition is acute heart failure.

67. The method of embodiment 601 wherein the cardiovascular condition is hypertension.

68. In another embodiment, the invention provides a method of improving cardiac contractility in a subject suffering from a cardiovascular condition, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-60, wherein cardiac contractility is improved in the subject after administration.

69. In another embodiment, the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-60, wherein the ejection fraction is increased in the subject after administration.

70. In another embodiment, the invention provides a method of treating a condition in a subject where it is desired to activate the APJ Receptor, the method comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof or the pharmaceutical composition of any one of embodiments 55-60.

71. The method of embodiment 70, wherein the condition is obesity or diabetes.

72. The method of embodiment 70, wherein the condition is diabetic nephropathy or chronic kidney disease.

73. The method of any one of embodiments 61-72, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

74. The method of any one of embodiments 61-72, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

75. In another embodiment, the invention provides a compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-60 for use in treating a cardiovascular condition.

76. The compound of embodiment 75, wherein the cardiovascular condition is heart failure.

77. The compound of embodiment 75, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

78. The compound of embodiment 75, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

79. The compound of embodiment 75, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

80. The compound of embodiment 75, wherein the cardiovascular condition is acute heart failure.

81. The compound of embodiment 75, wherein the cardiovascular condition is hypertension.

82. In another embodiment, the invention provides a compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-60 for use in activating the APJ Receptor or for treating a condition where it is desirable to activate the APJ Receptor.

83. The compound of embodiment 82, wherein the condition is obesity or diabetes.

84. The compound of embodiment 82, wherein the condition is diabetic nephropathy or chronic kidney disease.

85. In another embodiment, the invention provides a use of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof in the preparation of a medicament for treating a cardiovascular condition.

86. The use of embodiment 85, further comprising a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

87. The use of embodiment 85, further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

88. The use of the compound of embodiment 85, wherein the cardiovascular condition is heart failure.

89. The use of the compound of embodiment 85, wherein the cardiovascular condition is heart failure with reduced ejection fraction.

90. The use of the compound of embodiment 85, wherein the cardiovascular condition is heart failure with preserved ejection fraction.

91. The use of the compound of embodiment 85, wherein the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.

92. The use of the compound of embodiment 85, wherein the cardiovascular condition is acute heart failure.

93. The use of the compound of embodiment 845 wherein the cardiovascular condition is hypertension.

94. In another embodiment, the invention provides a use of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof in the preparation of a medicament for activating the APJ Receptor or treating a condition where it is desirable to activate the APJ Receptor.

95. The use of embodiment 94, wherein the condition is obesity or diabetes.

96. The use of embodiment 94, wherein the condition is diabetic nephropathy or chronic kidney disease.

97. In another embodiment, the invention provides a treatment regimen for a cardiovascular disease, the regimen comprising: the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

98. The treatment regimen of embodiment 97, wherein the regimen further comprises a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

99. The treatment regimen of embodiment 97, wherein the regimen further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

100. In another embodiment, the invention provides a kit, the kit comprising: the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the stereoisomer of any of the foregoing, or the mixture thereof.

101. The kit of embodiment 100, wherein the kit further comprises a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.

102. The kit of embodiment 100, wherein the kit further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).

103. In another embodiment, the invention provides a compound of Formula V, a salt thereof, a tautomer thereof, or a salt of the tautomer:

wherein:

R¹ is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents; and further wherein two R^(1a) substituents on adjacent carbon atoms of the phenyl R¹ group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1a′) substituent and may include an oxo substituent if the ring is not an aromatic ring;

R^(1a′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₈ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a) substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R³⁹)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—(CR^(3f)R^(3g))-Q, a group of formula —(C₃-C₈ cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h) substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈ cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R^(3h) substituents;

R^(3a) in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—Si(C₁-C₆ alkyl)₃, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with 1 or 2 oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents, and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO₂ moiety, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and

R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl).

104. The compound of embodiment 103, the salt thereof, the tautomer thereof, or the salt of the tautomer, wherein the compound has any of the R¹, R^(1a), R^(1a′), R^(1b′), R³, R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R^(3f), R^(3g), R^(3h), R⁴, R^(4a), R^(4b), Q, or R^(Q), values or combinations of values of any one of embodiments 2-54.

105. In another embodiment, the invention provides a method for preparing a compound of Formula VI, a salt thereof, a tautomer thereof, or a salt of the tautomer:

the method comprising:

-   -   a) cyclizing a compound of Formula V, a salt thereof, a tautomer         thereof, or a salt of the tautomer in the presence of an acid or         a base to form the compound of Formula VI, the salt thereof, the         tautomer thereof, or the salt of the tautomer,

wherein:

R¹ is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1a) substituents;

R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents; and further wherein two R^(1a) substituents on adjacent carbon atoms of the phenyl R¹ group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1a′) substituent and may include an oxo substituent if the ring is not an aromatic ring;

R^(1a′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₈ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl);

R^(1b′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl);

R³ is selected from an unsubstituted C₁-C₁₀ alkyl, a C₁-C₁₀ alkyl substituted with 1, 2, or 3 R^(3a) substituents, a group of formula —(CR^(3b)R^(3c))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—C(═O)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R^(3g))—CH(OH)-Q, a group of formula —(CR^(3d)R^(3e))—(CR^(3f)R³⁹)—(CR^(3f)R^(3g))-Q, a group of formula —(C₃-C₈ cycloalkyl)-Q, a group of formula -(heterocyclyl)-Q, or -Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R^(3h) substituents, and further wherein the C₃-C₈ cycloalkyl of the —(C₃-C₈ cycloalkyl)-Q group is unsubstituted or is substituted with 1 or 2 R^(3h) substituents;

R^(3a) in each instance is independently selected from —F, —Cl, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3b) and R^(3c) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—Si(C₁-C₆ alkyl)₃, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₈ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂;

R^(3h) in each instance is independently selected from —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)—(C₃-C₆ cycloalkyl), —C(═O)—O—(C₁-C₆ alkyl), oxo, or —C(═O)-(heterocyclyl), wherein the heterocyclyl group of the R^(h)—C(═O)-(heterocyclyl) has 5 or 6 ring members of which 1 or 2 are heteroatoms independently selected from N, or S or has 3 or 4 ring members of which 1 is a heteroatom selected from N, O, or S;

Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom;

R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with 1 or 2 oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl);

R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents, and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents;

R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl

R^(4a) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO₂ moiety, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl).

106. The method of embodiment 105, wherein R¹, R^(1a), R^(1a′), R^(1b′) R³, R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R^(3f), R^(3g), R^(3h), R⁴, R^(4a), R^(4b), Q, or R^(Q), have any of the values or combination of values of any one of embodiments 2-54.

107. The method of embodiment 105 or embodiment 106, wherein cyclizing further comprises heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer in the presence of the acid or the base.

108. The method of embodiment 107, wherein heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 50° C. to 100° C.

109. The method of embodiment 107, wherein heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer comprises heating the compound to a temperature of from 60° C. to 85° C.

110. The method of any one of embodiments 105-109, wherein the cyclizing of the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer is performed in the presence of the base.

111. The method of any one of embodiments 105-109, wherein the base is a metal hydroxide.

112. The method of embodiment 111, wherein the metal hydroxide is selected from NaOH or LiOH.

113. The method of any one of embodiments 110-112, wherein the cyclizing is carried out in an alcohol solvent.

114. The method of embodiment 113, wherein the alcohol is isopropanol.

115. The method of any one of embodiments 105-109, wherein cyclizing further comprises heating the compound of Formula V, the salt thereof, the tautomer thereof, or the salt of the tautomer in the presence of the acid.

116. The method of embodiment 115, wherein the acid is selected from a sulfonic acid, a carboxylic acid, polyphosphoric acid, phosphoric acid, sulfuric acid, or hydrochloric acid.

117. The method of embodiment 116, wherein the sulfonic acid is methanesulfonic acid.

118. The method of embodiment 116, wherein the acid is trifluoroacetic acid, acetic acid, or trichloroacetic acid.

119. The method of any one of embodiments 115-118, wherein the cyclizing is carried out in a cyclic ether, an acyclic ether, N,N-dimethylformamide, or acetonitrile.

120. The method of embodiment 119, wherein the cyclizing is carried out in a cyclic ether.

121. The method of embodiment 120, wherein the cyclic ether is selected from tetrahydrofuran, tetrahydropyran, or 1,4-dioxane.

122. The method of embodiment 120, wherein the cyclic ether is 1,4-dioxane.

In some embodiments, the compound is a salt. Such salts may be anhydrous or associated with water as a hydrate. In some embodiments, the compound may be in a neutral form as a base or an acid.

Also provided are pharmaceutical compositions that include the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments is present in an amount effective for the treatment of a cardiovascular condition or other condition such as obesity or diabetes, for activating the APJ Receptor. In some embodiments, the pharmaceutical composition is formulated for oral delivery whereas in other embodiments, the pharmaceutical composition is formulated for intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once a day or QD, and in some such formulations is a tablet where the effective amount of the active ingredient ranges from 5 mg to 60 mg, from 6 mg to 58 mg, from 10 mg to 40 mg, from 15 mg to 30 mg, from 16 mg to 25 mg, or from 17 mg to 20 mg. In some such compositions, the amount of active ingredient is 17 mg.

In some embodiments, the subject is a mammal. In some such embodiments, the mammal is a rodent. In other such embodiments, the mammal is a canine. In still other embodiments, the subject is a primate and, in some such embodiments, is a human.

The pharmaceutical compositions or formulations for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.

The compounds of the invention can be administered to provide systemic distribution of the compound within the patient. Therefore, in some embodiments, the compounds of the invention are administered to produce a systemic effect in the body.

As indicated above, the compounds of the invention may be administered via oral, mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration. In some embodiments, the compounds of the invention are administered via mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration. In other embodiments, the compounds of the invention are administered via oral administration. In still other embodiments, the compounds of the invention are not administered via oral administration.

The compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof may find use in treating a number of conditions. For example, in some embodiments, the invention comprises methods or uses that include the use or administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention, in treating a subject suffering from a cardiovascular condition. In some embodiments, the cardiovascular condition includes, but is not limited to, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling after cardiac surgery, valvular heart disease, hypertension including, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension, aortic aneurysm such as abdominal aortic aneurysm, or atrial fibrillation including improving arrhythmia. In some embodiments, the cardiovascular condition is heart failure. In some such embodiments, the heart failure is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction. In other such embodiments the subject may have systolic heart failure or chronic diastolic heart failure and is thus useful in treating heart failure patients with systolic dysfunction and in treating heart failure patients with diastolic dysfunction. In some embodiments, the cardiovascular condition may be acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.

As noted, the compounds of the invention may be used to treat a number of diseases and disorders. Thus, in some embodiments, the invention provides a method of treating a disease or disorder selected from acute decompensated heart failure, chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes, gestational diabetes, obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries, sunburn, and preeclampsia in a subject. Such methods include administering a compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, a mixture thereof, or a pharmaceutical composition that includes any of these to a subject in need thereof.

In some embodiments, the invention provides a method of improving cardiac contractility in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in cardiac contraction may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improving cardiac relaxation in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in cardiac relaxation may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of improving ventricular arterial coupling in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The improvement in ventricular arterial coupling may lead to significant improvements in methods for treating heart failure patients.

In some embodiments, the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.

The compounds of the invention may also find potential benefit in improving cardiac relaxation and thus find utility in treating certain heart failure patients. The compounds of the invention may thus find utility in improving inotropic function in some embodiments and may also find utility in improving lusitropic function.

In some embodiments, the invention provides a method of treating condition in a subject where it is desired to activate the APJ Receptor. Such methods include administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. In some such embodiments, the condition is obesity or diabetes whereas in other embodiments, the condition is diabetic nephropathy or chronic kidney disease. In some such embodiments, the condition is type II diabetes. In other embodiments, the condition is cardiac wasting.

The compounds of the invention may find utility in treating a number of other conditions. For example, the compounds of the invention may find utility in treating patients with conditions related to renal perfusion, hyperglycemia, aquaresis, and diuresis. In some embodiments, the invention provides a method of treating one of these subjects that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject. The compounds of the invention may further find utility in arginine vasopressin (AVP) regulation and in angiotensin receptor (AT 1R) regulation.

The compounds of the invention may find utility in treating a number of other conditions or producing desired outcomes or results. For example, the compounds of the invention may find utility in activating stem cells, more specifically cardiac stem cells, and even more specifically endogenous cardiac stem cells. Thus, the compounds of the invention may find utility in activating heart stem cells in a subject such as in a human patient. The compounds of the invention may yet further find utility in regrowing tissue and in assisting functional recovery after transplanting cells such as cells with bone marrow-derived mesenchymal stem cells. The compounds of the invention may also find utility in increasing cardiac stem cell proliferation and may be used to do such in patients that have suffered a myocardial infarction. As another example, the compounds of the invention may find utility in reducing infarct size, in promoting cardiac repair, and in activating stem cells and progenitors in post-myocardial infarction subjects. As still yet another example, the compounds of the invention may be used during surgery such as heart bypass surgery or heart transplant procedures as a therapeutic to reduce reperfusion injury. In some embodiments, the invention provides a method of treating one of these subjects or improving the condition in a subject that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.

Some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention). Thus, the compounds of the invention can be used in combination with at least one other therapeutic agent. Examples of additional therapeutic agents include, but are not limited to, antibiotics, anti-emetic agents, antidepressants, antifungal agents, anti-inflammatory agents, antineoplastic agents, antiviral agents, cytotoxic agents, and other anticancer agents, immunomodulatory agents, alpha-interferons, β-interferons, alkylating agents, hormones, and cytokines. In one embodiment, the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension.

As described above some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention). In some embodiments, the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension. In some embodiments, the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent such as, but not limited to, an α-blocker, a α-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, a neutral endopeptidase (NEP) inhibitor, a vasodilator, an aldosterone antagonist, a natriuretic, a saluretic, a centrally acting hypertensive, an aldosterone synthase inhibitor, or an endothelin receptor antagonist. In some embodiments, the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor. In some such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB). In some such embodiments, the additional therapeutic agent is thus an angiotensin converting enzyme (ACE) inhibitor whereas in others it is an angiotensin-receptor blocker (ARB). In other such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as a neutral endopeptidase (NEP) inhibitor. In other such embodiments, the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an inhibitor of the funny current. In some embodiments, the method of use may include two or more additional therapeutic agents. For example, in some embodiments, the invention may include a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and additional therapeutic agents such as an ACE inhibitor and a NEP inhibitor.

Therapeutic agents such as α-blockers may be used in conjunction with the compounds of the invention. Examples of α-blockers include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin and their pharmaceutically acceptable salts.

Therapeutic agents such as α-blockers may be used in conjunction with the compounds of the invention. Examples of α-blockers include, but are not limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, and their pharmaceutically acceptable salts.

Calcium channel blockers may also be used as therapeutic agents in conjunctions with the compounds of the present invention. Examples of calcium channel blockers, include, but are not limited to, dihydropyridines (DHPs) and non-DHPs. Examples of DHPs include, but are not limited to, amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts. Examples of Non-DHPs include, but are not limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceutically acceptable salts.

Diuretics may also be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorthiazide, and methylchlorothiazide and pharmaceutically acceptable salts thereof.

Centrally acting hypertensive agents may also be used in conjunction with the compounds of the present invention. Examples, include, but are not limited to, clonidine, guanabenz, guanfacine, methyldopa, and pharmaceutically acceptable salts thereof.

ACE inhibitors may be used in conjunction with the compounds of the present invention. Examples of ACE inhibitors that may be used include, but are not limited to, alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, Lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril, and zofenopril and their pharmaceutically acceptable salts. Examples of some dual ACE/NEP inhibitors include, but are not limited to omapatrilat, fasidotril, and fasidotrilat and their pharmaceutically acceptable salts.

ARBs may also be used as therapeutic agents in conjunction with the compounds of the present invention. Examples of ARBs include, but are not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan and their pharmaceutically acceptable salts. Examples of some dual ARB/NEP inhibitors include, but are not limited to combinations of valsartan and sacubitril and their pharmaceutically acceptable salts.

NEP inhibitors may also be used as therapeutic agents in conjunction with the compounds of the present invention. An example of a NEP inhibitor includes, but it not limited to, sacubitril and its pharmaceutically acceptable salts.

Aldosterone synthase inhibitors may also be used as therapeutic agents in combination with the compounds of the present invention. Examples of aldosterone synthase inhibitors include, but are not limited to, anastrozole, fadrozole, and exemestane and their pharmaceutically acceptable salts.

Endothelin antagonists are other therapeutic agents that may be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, and tezosentan, and their pharmaceutically acceptable salts.

Inhibitors of the funny current (I_(f)) may also be used in conjunction with the compounds of the invention. An example of an inhibitor of the funny current is ivabradine and its pharmaceutically acceptable salts.

Myosin activators may also be used in conjunction with the compounds of the invention. Examples of myosin activators include cardiac myosin activators.

It will be recognized that for purposes of this application, a therapeutic agent other than one of the present invention includes compounds such as known prodrugs that are converted into the therapeutic agent after administration. For example, a compound without antineoplastic activity, but that is converted into an antineoplastic agent in the body after administration, may be administered along with a compound of the invention. As another example, sacubitril is considered a NEP inhibitor for the purposes of this application even though it is a prodrug that is converted into sacubitrilat by de-ethylation via esterases.

When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The phrase “co-therapy” (or “combination-therapy”), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cardiovascular conditions.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of any of the embodiments described herein may also be administered sequentially with known agents for use in treating cardiovascular conditions such as heart failure and hypertension when a combination formulation is inappropriate. The invention is not limited in the sequence of administration as compounds of the invention may be administered either prior to, simultaneous with, or after administration of a known therapeutic agent.

Therapeutic agents such as α-blockers may be used in conjunction with the compounds of the invention. Examples of α-blockers include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin and their pharmaceutically acceptable salts.

Therapeutic agents such as α-blockers may be used in conjunction with the compounds of the invention. Examples of α-blockers include, but are not limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, and their pharmaceutically acceptable salts.

Calcium channel blockers may also be used as therapeutic agents in conjunctions with the compounds of the present invention. Examples of calcium channel blockers, include, but are not limited to, dihydropyridines (DHPs) and non-DHPs. Examples of DHPs include, but are not limited to, amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts. Examples of Non-DHPs include, but are not limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceutically acceptable salts.

Diuretics may also be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorthiazide, and methylchlorothiazide and pharmaceutically acceptable salts thereof.

Centrally acting hypertensive agents may also be used in conjunction with the compounds of the present invention. Examples, include, but are not limited to, clonidine, guanabenz, guanfacine, methyldopa, and pharmaceutically acceptable salts thereof.

ACE inhibitors may be used in conjunction with the compounds of the present invention. Examples of ACE inhibitors that may be used include, but are not limited to, alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, Lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril, and zofenopril and their pharmaceutically acceptable salts. Examples of some dual ACE/NEP inhibitors include, but are not limited to omapatrilat, fasidotril, and fasidotrilat and their pharmaceutically acceptable salts.

ARBs may also be used as therapeutic agents in conjunction with the compounds of the present invention. Examples of ARBs include, but are not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan and their pharmaceutically acceptable salts. Examples of some dual ARB/NEP inhibitors include, but are not limited to combinations of valsartan and sacubitril and their pharmaceutically acceptable salts.

NEP inhibitors may also be used as therapeutic agents in conjunction with the compounds of the present invention. An example of a NEP inhibitor includes, but it not limited to, sacubitril and its pharmaceutically acceptable salts.

Aldosterone synthase inhibitors may also be used as therapeutic agents in combination with the compounds of the present invention. Examples of aldosterone synthase inhibitors include, but are not limited to, anastrozole, fadrozole, and exemestane and their pharmaceutically acceptable salts.

Endothelin antagonists are other therapeutic agents that may be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, and tezosentan, and their pharmaceutically acceptable salts.

Inhibitors of the funny current (I_(f)) may also be used in conjunction with the compounds of the invention. An example of an inhibitor of the funny current is ivabradine and its pharmaceutically acceptable salts.

Myosin activators may also be used in conjunction with the compounds of the invention. Examples of myosin activators include cardiac myosin activators.

It will be recognized that for purposes of this application, a therapeutic agent other than one of the present invention includes compounds such as known prodrugs that are converted into the therapeutic agent after administration. For example, a compound without antineoplastic activity, but that is converted into an antineoplastic agent in the body after administration, may be administered along with a compound of the invention. As another example, sacubitril is considered a NEP inhibitor for the purposes of this application even though it is a prodrug that is converted into sacubitrilat by de-ethylation via esterases.

When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. The phrase “co-therapy” (or “combination-therapy”), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cardiovascular conditions.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of any of the embodiments described herein may also be administered sequentially with known agents for use in treating cardiovascular conditions such as heart failure and hypertension when a combination formulation is inappropriate. The invention is not limited in the sequence of administration as compounds of the invention may be administered either prior to, simultaneous with, or after administration of a known therapeutic agent.

The invention is further described by reference to the following examples, which are intended to exemplify the claimed invention but not to limit it in any way.

EXAMPLES

Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere. Purity was measured using Agilent 1100 Series high performance liquid chromatography (HPLC) systems with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6×150 mm, 5 micron, 5 to 100% ACN in H₂O with 0.1% TFA for 15 min at 1.5 mL/min; System B: Zorbax SB-C8, 4.6×75 mm, 10 to 90% ACN in H₂O with 0.1% formic acid for 12 min at 1.0 mL/min). Silica gel chromatography was generally performed with prepacked silica gel cartridges (Biotage or Teledyne-Isco). ¹H NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer or a Varian 400 MHz spectrometer at ambient temperature, or the NMR spectra were collected with a Bruker Avance III spectrometer operating at a proton frequency of 500.13 MHz using a 10 L Protasis CapNMR flow probe. NMR samples were delivered to the flow probe using a Protasis One-Minute NMR™ Automation system comprised of a Discovery Tower™ Sample Manager and a Waters Liquid Handler made by CTC, Switzerland (Model 2777). All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or another internal reference in the appropriate solvent indicated. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constants, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 Series LC-MS with UV detection at 254 nm and 215 nm and a low resonance electrospray mode (ESI).

A wide variety of sulfonamide tails and R⁴ groups can be used to synthesize compounds of the invention such as those set forth in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which are hereby incorporated by reference in their entireties and for all purposes as if specifically set forth herein. Thus, compounds of the present invention may be prepared using any of the R³, R⁴, and Q groups taught in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336.

The following Abbreviations are used to refer to various reagents and solvents:

-   ACN Acetonitrile -   AcOH Acetic Acid -   d day or days -   DCM Dichloromethane -   (DHQD)₂PHAL     1,4-Bis[(S)-[(2R,4S,5R)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine -   DIEA N,N-Diisopropylethylamine -   DMF N,N-Dimethylformamide -   DMAc Dimethylacetamide -   DMSO Dimethylsulfoxide -   EtOAc Ethyl Acetate -   EtOH Ethanol -   EtOTf Ethyl trifluoromethanesulfonate -   h hour or hours -   IPA Isopropanol -   MeOH Methanol -   MeOTf Methyl trifluoromethanesulfonate -   min minute or minutes -   RT Room temperature -   SFC Supercritical fluid chromatography -   TBSOTf t-butyldimethylsilyl trifluoromethanesulfonate -   TEA Triethylamine -   TFA Trifluoroacetic acid -   THF Tetrahydrofuran -   TLC Thin Layer Chromatography

Example 1.1. Preparation of 5-isothiocyanato-4,6-dimethoxypyrimidine

5-Isothiocyanato-4,6-dimethoxypyrimidine, Example 1.1

To a stirred solution of 1,1″-thiocarbonyldi-2(1H)-pyridone (Aldrich, 14.97 g, 64.5 mmol) in dry DCM (75 mL), a solution of 4,6-dimethoxypyrimidin-5-amine (D-L chiral chemicals, 10 g, 64.5 mmol) in DCM (75 mL) was added dropwise via an addition funnel at RT over 40 min. The reaction was further stirred for 16 h. The reaction was concentrated in vacuo and purified on silica gel (0-30% EtOAc in heptanes) to give 5-isothiocyanato-4,6-dimethoxypyrimidine (12.75 g, 64.7 mmol, 100% yield) as a white solid. LCMS (pos.) m/z: 198.1 (M+H)⁺.

Example 1.2. Preparation of 2-isothiocyanato-1,3-dimethoxybenzene

2-Isothiocyanato-1,3-dimethoxybenzene, Example 1.2

To a solution of 2,6-dimethoxyaniline (500 g, 3.25 mol, 1 eq) in DCM (5.0 L) was added 2,6-lutidine (1.5 L, 13.0 mol, 4 eq). The reaction mixture was cooled to 0° C. (internal temperature) and CSCl₂ (374 mL, 4.88 mol, 1.5 eq) was added drop-wise. The reaction mixture was allowed to stir for 2 h. The solvent was evaporated under reduced pressure and the initial product was purified by SiO₂ column to provide the title compound, 2-isothiocyanato-1,3-dimethoxybenzene, Example 1.2 as white solid (1.06 g, 2.80 mol, 86%). LCMS (ESI pos. ion) m/z: (M+H)⁺=196. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t, J=8.48 Hz, 1H), 6.55 (d, J=8.48 Hz, 2H), 3.90 (m, 6H).

The compounds set forth in the following table were synthesized following the procedure in Example 1.2 using the known starting material as described.

TABLE 1 Example Reagents Structure, Name and Data 1.22 Commercially available from Sigma Aldrich

1-isothiocyanato-2-methoxybenzene. ¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (s, 3H), 6.96 (td, J = 7.68, 1.27 Hz, 1H), 7.16 (dd, J = 8.31, 1.27 Hz, 1H), 7.30 (dd, J = 7.92, 1.66 Hz, 1H),7.31-7.37 (m, 1H). 1.23 3,5-difluoropyridin-4- amine (commercially available from Ark Pharm Inc, Libertyville. IL)

3,5-difluoro-4-isothiocyanatopyridine. LCMS-ESI (pos.) m/z: 173.0 (M + H)⁺.

Example 1.0. Preparation of. (1R,2S)—N-(5-(3-bromophenyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1 l-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(1R,2S)—N-(5-(3-Bromophenyl)-4-(4,6-dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 1.0

In a 50 mL RBF containing Example 103.0 (74 mg, 0.302 mmol) in ACN (3.0 mL) was added 5-isothiocyanato-4,6-dimethoxypyrimidine, Example 1.1 (60.7 mg, 0.308 mmol) and cesium carbonate (128 mg, 0.392 mmol). The vial was sealed and stirred at RT for 18 h. To the reaction above was added 3-bromobenzohydrazide (Frontier Scientific Services Inc., 64.9 mg, 0.302 mmol) and silver(I) nitrate (Alfa Aesar, 102 mg, 0.603 mmol) and the reaction sealed and stirred at RT for 2 h. After which, the reaction was filtered through Celite® filter aid, the filter cake was washed with ACN (3×3 mL), DCM (2×3 mL) and the filtrates concentrated in vacuo to give the product, which was used in the next step without purification.

To the above product dissolved in 1,4-dioxane (3 mL) was added methanesulfonic acid (Aldrich, 48.9 μL, 0.754 mmol) dropwise. The reaction mixture was stirred at 80° C. for 15 h. After cooling to RT, the reaction mixture was treated with saturated NaHCO₃ (2 mL) until pH 8. The solution was extracted with EtOAc (3×10 mL), and the organic layers were combined, dried (Na₂SO₄), and concentrated. The product was purified by chromatography through a Biotage 10 g ultra column, eluting with a gradient of 0% to 20% 3:1 EtOAc/EtOH in DCM, followed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H₂O, gradient 10% to 70% over 15 min to provide the TFA salt of the title compound (42.6 mg, 0.070 mmol, 23% yield) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 2H), 8.50 (s, 1H), 7.64-7.70 (m, 1H), 7.57-7.62 (m, 1 H), 7.16-7.27 (m, 2H), 5.01 (d, J=4.50 Hz, 1H), 3.98 (s, 3H), 3.98 (s, 3H), 3.68-3.82 (m, 1H), 3.35 (s, 3H), 2.39 (s, 3H), 1.39 (d, J=6.85 Hz, 3H). LCMS (pos.) m/z: 605.0, 607.0 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 1.0 using the known starting material as described.

TABLE 2 Example Reagents Structure, Name and and Data 2.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 103.0), 5- isothiocyanato-4,6- dimethoxypyrimidine, Example 1.1, 3-cyanobenzohydrazide (commerically available from Matrix Scientific).

(1R,2S)-N-(5-(3-cyanophenyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 2 H), 8.50 (s, 1 H), 7.70-7.78 (m, 2 H), 7.60 (d, J = 8.02 Hz, 1 H), 7.45-7.54 (m, 1 H), 4.98 (d, J = 4.50 Hz, 1 H), 3.96 (s, 3H), 3.96 (s, 3H), 3.68-3.79 (m, 1 H), 3.33 (s, 3 H), 2.37 (s, 3 H), 1.37 (d, J = 7.04 Hz, 3 H). LCMS (pos.) m/z: 552.0 (M + H)⁺. 3.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 103.0), 5- Isothiocyanato-4,6- dimethoxypyrimidine, Example 1.1, 3-chlorobenzhydrazide (commerically available from *Acros Organics).

(1R,25)-N-(5-(3-chlorophenyl)-4-(4,6- dimethoxypyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methylpyrimidin-2-yl)propane-2- sulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 2 H), 8.48 (s, 1 H), 7.39-7.50 (m, 2 H), 7.27-7.32 (m, 1 H), 7.22 (s, 1 H), 4.98 (d, J = 4.50 Hz, 1 H), 3.96 (s, 3H), 3.96 (s, 3H), 3.67-3.81 (m, 1 H), 3.33 (s, 3 H), 2.36 (s, 3 H), 1.37 (d, J = 7.04 Hz, 3 H). LCMS (pos.) m/z: 561.0 (M + H)⁺. 4.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 103.0), 5- Isothiocyanato-4,6- dimethoxypyrimidine, Example 1.1, benzhydrazide (commerically available from Frontier Scientific Services Inc.).

(1R,2S)-N-(4-(4,6-dimethoxypyrimidin-5-yl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2-sulfonamide. ¹H NMR (300 MHz, CDCl₃) δ 11.19 (br. s., 1 H), 8.58-8.66 (m, 2 H), 8.47 (s, 1 H), 7.32-7.53 (m, 5 H), 4.98 (d, J = 4.68 Hz, 1 H), 3.94 (s, 3H), 3.94 (s, 3H), 3.69-3.84 (m, 1 H), 3.37 (s, 3 H), 2.34 (s, 3 H), 1.42 (d, J = 7.02 Hz, 3 H). LCMS (pos.) m/z: 527.0 (M + H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 3 Example Reagents Structure, Name and Data 5.0 (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 102.0), benzhydrazide (Acros Organics), 5- isothiocyanato-4,6- dimethoxy pyrimidine (Example 1.1).

(2S,3R)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.44 (1 H, s) 8.67 (1 H, s) 8.60 (2 H, s) 7.49-7.56 (1 H, m) 7.42-7.49 (2 H, m) 7.36-7.41 (2 H, m) 3.88 (3 H, s) 3.87 (3 H, s) 3.57- 3.74 (2 H, m) 2.24 (3 H, s) 1.25 (3 H, d, J = 7.00 Hz) 1.12 (3 H, d, J = 6.95 Hz). LCMS-ESI (pos.) m/z: 511.2 (M + H)⁺. 6.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 103.0), m- anisic hydrazide (Maybridge Chemical Co.. Ltd.), 5- isothiocyanato-4,6- dimethoxypyrimidine, Example 1.1.

(1R,2S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3- methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy- 1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.18 (1 H, br s) 8.61 (2 H, s) 8.47 (1 H, s) 7.22-7.26 (1 H, m) 6.95- 7.01 (2 H, m) 6.90-6.94 (1 H, m) 4.97 (1 H, d, J = 4.56 Hz) 3.96 (3 H, s) 3.93 (3 H, s) 3.73-3.78 (4 H, m) 3.36 (3 H, s) 2.33 (3 H, s) 1.40 (3 H, d, J = 7.00 Hz). LCMS-ESI (pos.) m/z: 557.2 (M + H)⁺. 7.0 (S)-1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide or (R)- 1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide (Example 111.6), benzhydrazide (Acros Organics), 2- isothiocyanato-1,3- dimethoxybenzene (Example 1.2.)

(2S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2- propanesulfonamide or (2R)-N-(4-(2,6- dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)- 1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (1 H, s) 8.84(2 H, d, J = 0.83 Hz) 7.41-7.50 (2 H, m) 7.31- 7.40 (4 H, m) 6.81 (2 H, dd, J = 8.63, 1.17 Hz) 3.69 (3 H, s) 3.68 (3 H, s) 3.44-3.52 (2 H, m) 2.84 (1 H, dd, J = 15.06, 11.32 Hz) 1.10 (3 H, d, J = 6.69 Hz). LCMS-ESI (pos.) m/z: 499.2 (M + H)⁺. 8.0 (S)-1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide or (R)- 1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide (Example 111.0), benzhydrazide (Acros Organics), 2- isothiocyanato-1,3- dimethoxybenzene (Example 1.2).

(2S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2- propanesulfonamide or (2R)-N-(4-(2,6- dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)- 1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (1 H, s) 8.84 (2 H, d, J = 0.78 Hz) 7.42-7.50 (2 H, m) 7.31- 7.41 (4 H, m) 6.81 (2 H, dd, J = 8.60, 1.14 Hz) 3.69 (3 H, s) 3.68 (3 H, s) 3.42-3.53 (2 H, m) 2.79- 2.89 (1 H, m) 1.10 (3 H, d, J = 6.63 Hz). LCMS-ESI (pos.) m/z: 499.2 (M + H)⁺. 9.0 (S)-1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide or (R)- 1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide (Example 111.6), benzhydrazide (Acros Organics), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

(2S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2- pyrimidinyl)-2-propanesulfonamide or (2R)-N-(4- (4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO- d₆) δ 12.91-13.84 (1 H, m) 8.83 (1 H, s) 8.66 (1 H, s) 7.41-7.54 (3 H, m) 7.38 (2 H, br d, J = 7.33 Hz) 3.85-3.95 (6 H, m) 3.49-3.62 (2 H, m) 2.85 (1 H, dd, J = 14.24, 10.28 Hz) 2.52-2.55 (1 H, m) 1.12 (3 H, d, J = 6.68 Hz). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 10.0 2-(2-cyano-4- fluorophenyl)ethanesulfonamide (Example 112.0), benzhydrazide (Acros Organics), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

2-(2-cyano-4-fluorophenyl)-N-(4-(4,6-dimethoxy- 5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3- yl)ethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.58 (1 H, s) 8.65 (1 H, s) 7.77-7.82 (1 H, m) 7.43-7.57 (5 H, m) 7.33-7.41 (2 H, m) 3.89 (6 H, s) 3.32-3.39 (2 H, m) 3.08-3.17 (2 H, m). LCMS-ESI (pos.) m/z: 510.2 (M + H)⁺. 11.0 (S)-1-(5-fluoropyrimidin-2- yl)propane-2-sulfonimide or (R)- 1-(5-fluoropyrimidin-2- yl)propane-2-sulfonamide (Example 111.0), benzhydrazide (Acros Organics), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

(2S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2- pyrimidinyl)-2-propanesulfonamide or (2R)-N-(4- (4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO- d₆) δ 12.91-13.84 (1 H, m) 8.83 (1 H, s) 8.66 (1 H, s) 7.41-7.54 (3 H, m) 7.38 (2 H, br d, J = 7.33 Hz) 3.85-3.95 (6 H, m) 3.49-3.62 (2 H, m) 2.85 (1 H, dd, J = 14.24, 10.28 Hz) 2.52-2.55 (1 H, m) 1.12 (3 H, d, J = 6.68 Hz). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 12.0 2-(2-cyano-4- fluorophenyl)ethanesulfonamide (Example 112.0), benzhydrazide (Acros Organics), 2- isothiocyanato-1,3- dimethoxybenzene (Example 1.2).

2-(2-cyano-4-fluorophenyl)-N-(4-(2,6- dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3- yl)ethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (1 H, s) 7.81 (1 H, dd, J = 8.66, 2.49 Hz) 7.42-7.57 (4 H, m) 7.30-7.42 (4 H, m) 6.83 (1 H, s) 6.80 (1 H, s) 3.33 (6 H, s) 3.24-3.31 (2 H, m) 3.09-3.15 (2 H, m). LCMS-ESI (pos.) m/z: 507.2 (M + H)⁺. 13.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 104.0), benzhydrazide (Acros Organics), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2).

(1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl- 2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (1 H, s) 8.67 (2 H, s) 7.42-7.51 (2 H, m) 7.30-7.41 (4 H, m) 6.82 (2 H, d, J = 8.60 Hz) 4.71 (1 H, d, J = 7.36 Hz) 3.73 (3 H, s) 3.72 (3 H, s) 3.37-3.47 (2 H, m) 2.28 (3 H, s) 1.00 (3 H, d, J = 6.01 Hz) 0.94 (3 H, d, J = 7.05 Hz) 0.80 (3 H, d, J = 6.17 Hz). LCMS-ESI (pos.) m/z: 553.2 (M + H)⁺. 14.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 104.0), benzhydrazide (Acros Organics), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

(1S,2S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-(1-methylethoxy)- 1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.35 (1 H, s) 8.67 (2 H, s) 8.66 (1 H, s) 7.42-7.53 (3 H, m) 7.37 (2 H, d, J = 7.40 Hz) 4.70 (1 H, d, J = 7.46 Hz) 3.92 (3 H, s) 3.92 (3 H, s) 3.45 (1 H, br t, J = 7.17 Hz) 3.37 (1 H, dt, J = 12.13, 6.07 Hz) 2.28 (3 H, s) 0.98 (3 H, d, J = 6.03 Hz) 0.95 (3 H, d, J = 7.01 Hz) 0.79 (3 H, d, J = 6.10 Hz). LCMS-ESI (pos.) m/z: 555.2 (M + H)⁺. 15.0 (2S,3R)-3-(5-methylpyrimidin-2- yl)butane-2-sulfonamide (Example 102.0), benzhydrazide (Acros Organics), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2).

(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2- butanesulfonamide. ¹H NMR (400 MHz, DMSO- d₆) δ 13.18 (1 H, s) 8.60 (2 H, s) 7.42-7.51 (2 H, m) 7.30-7.41 (4 H, m) 6.81 (2 H, dd, J = 8.55, 3.52 Hz) 3.67 (7 H, s) 3.61 (1 H, br s) 2.24 (3 H, s) 1.24 (3 H, d, J = 7.10 Hz) 1.10 (3 H, d, J = 6.95 Hz). LCMS-ESI (pos.) m/z: 509.2 (M + H)⁺. 16.0 (2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 102.4), benzhydrazide (Acros Organics), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2).

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)- 2-butanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (1 H, s) 8.87 (2 H, s) 7.42-7.50 (2 H, m) 7.32-7.40 (4 H, m) 6.81 (2 H, dd, J = 8.58, 3.34 Hz) 3.69 (4 H, s) 3.68 (3 H, s) 3.53-3.61 (1 H, m) 1.25 (3 H, d, J = 7.10 Hz) 1.13 (3 H, d, J = 6.95 Hz). LCMS-ESI (pos.) m/z: 511.2 (M + H)⁺. 17.0 (2S,3R)-3-(5-chloropyrimidin-2- yl)butane-2-sulfonamide (Example 102.4), benzhydrazide (Acros Organics), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-2-butanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.42 (1 H, s) 8.88 (2 H, s) 8.66 (1 H, s) 7.41-7.55 (3 H, m) 7.37 (2 H, m, J = 7.60 Hz) 3.89 (4 H, s) 3.87 (3 H, br s) 3.63-3.71 (1 H, m) 1.27 (3 H, br d, J = 6.89 Hz) 1.11-1.17 (3 H, m). LCMS-ESI (pos.) m/z: 531.2 (M + H)⁺. 18.0 (1R,2S)-1-((tert- butyldimethylsilyl)oxy)-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 113.0), benzhydrazide (Acros Organics), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2) The silyl protecting group was rcmoved in situ during base mediated cyclodehydration step.

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-hydroxy-1-(5-methyl-2- pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.15 (1 H, br s) 8.64 (2 H, s) 7.38-7.49 (1 H, m) 7.33 (4 H, br s) 6.80 (2 H, dd, J = 8.42, 2.00 Hz) 5.00-5.28 (2 H, m) 3.67 (4 H, br s) 3.66 (3 H, br s) 3.52-3.63 (1 H, m) 2.27 (3 H, s). LCMS-ESI (pos.) m/z: 511.2 (M + H)⁺. 19.0 2-(4- chlorophenyl)ethanesulfonamide (Aurora Fine Chemicals LLC), benzhydraxide (Acros Organics), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

2-(4-chlorophenyl)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3- yl)ethanesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.48 (1 H, s) 8.61 (1 H, s) 7.44-7.48 (1 H, m) 7.40 (2 H, t, J = 7.41 Hz) 7.27-7.34 (4 H, m) 7.18-7.21 (2 H, m) 3.83 (6 H, s) 3.17-3.22 (2 H, m) 2.83-2.88 (2 H, m). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 20.0 (1R,2S)-1-((tert- butyldimethylsilyl)oxy)-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 113.0), benzhydrazide (Acros Organics), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1). The silyl protecting group was removed in situ during base mediated cyclode hydration step.

(1R,2S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-hydroxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.35 (1 H, s) 8.65 (1 H, s) 8.64 (2 H, s) 7.49-7.53 (1 H, m) 7.45 (2 H, t, J = 7.59 Hz) 7.37 (2 H, d, J = 7.32 Hz) 5.19 (1 H, d, J = 5.71 Hz) 5.09-5.14 (1 H, m) 3.88 (3 H, s) 3.87 (3 H, s) 3.58 (1 H, dd, J = 7.01, 3.76 Hz) 2.27 (3 H, s) 1.12 (3 H, d, J = 7.01 Hz). LCMS-ESI (pos.) m/z: 513.1 (M + H)⁺.

Example 21.0. Preparation of (3S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide or (3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide

(S)-1-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide and (R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Example 21.1

A 100 mL round bottom flask was charged with piperidine-3-sulfonamide hydrochloride (1.0 g, 4.98 mmol, Frontier Scientific) and dissolved in DMSO (25.0 mL). To that solution was added 2-chloro-5-fluoropyrimidine (3.30 g, 24.91 mmol, Frontier Scientific) followed by Hunig's base (8.67 mL, 49.8 mmol). The flask was fitted with a condenser and placed into a reaction block preheated to 100° C. After 2 h, the reaction was cooled to RT and diluted with DCM and water and transferred into a separatory funnel where the layers were separated. The organic layer was washed with water (×3) and brine (×2). The combined aqueous phase was extracted with DCM (×2) and subsequently discarded. The combined organic layers were washed with brine (×1), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give a pink solid. The solids were triturated with IPA to give 1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide (623 mg, 2.39 mmol, 48.0% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (2H, d, J=0.83 Hz) 6.93 (2H, s) 4.94-5.06 (1H, m) 4.56 (1H, br d, J=12.23 Hz) 2.88-3.00 (2H, m) 2.81 (1H, td, J=12.83, 2.75 Hz) 2.18 (1H, br d, J=12.75 Hz) 1.76-1.85 (1H, m) 1.63-1.75 (1H, m) 1.38-1.52 (1H, m).

(S)-1-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Example 21.2. A chiral SFC purification of Example 21.1 was performed. Preparative SFC method: Column: Chiralpak AD-H (20×150 mm), Mobile Phase: 65:35 (A:B), A: Liquid CO₂, B: MeOH, Flow Rate: 80 mL/min, 243 nm, 100 bar inlet pressure and provided two peaks of >99.5% ee: The first eluting peak was assigned Example 21.2. LCMS-ESI (pos.) m/z: 261.2 (M+H)⁺. Peak assignment determined by analytical SFC: Chiralpak AD-H, 30% MeOH Rf: 1.14 min.

(S)-1-(5-Fluoropyrimidin-2-yl)piperidine-3-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)piperidine-3-sulfonamide, Example 21.3

The second eluting peak described in the conditions described in Example 21.2 was assigned Example 21.3. LCMS-ESI (pos.) m/z: 261.2 (M+H)⁺. Peak assignment determined by analytical SFC: Chiralpak AD-H, 30% MeOH Rf: 1.83 min.

(S,Z)-2-Benzoyl-N′-(2,6-dimethoxyphenyl)-N-((1-(5-fluoropyrimidin-2-yl)piperidin-3-yl)sulfonyl)hydrazinecarboximidamide or (R,Z)-2-benzoyl-N′-(2,6-dimethoxyphenyl)-N-((1-(5-fluoropyrimidin-2-yl)piperidin-3-yl)sulfonyl)hydrazinecarboximidamide, Example 21.4

A 2-dram pressure rated vial was charged with Example 21.3 (50 mg, 0.192 mmol) and 2-isothiocyanato-1,3-dimethoxybenzene (Example 1.2, 37.9 mg, 0.194 mmol, Example 1.2). The mixture was dissolved in ACN (960 μL) and cesium carbonate (94 mg, 0.288 mmol) was added in one portion at RT. After 24 h, the thick white slurry was diluted with ACN (960 μL) and benzhydrazide (26.4 mg, 0.194 mmol) was added followed by silver nitrate (0.384 mmol). The white slurry immediately turned brown and after several min black. After 10 min, the reaction mixture was poured directly onto a Biotage column and purified by flash chromatography: Biotage SNAP Ultra—CV=85 mL, eluting with EtOAc:EtOH 3:1 (v/v) in heptane 0% (1CV), 0-100% (10CV), 100% (35 V) to provide the title compound (107 mg, 0.192 mmol, 100% yield) as an white solid. LCMS-ESI (pos.) m/z: 558.2 (M+H)⁺.

(3S)—N-(4-(2,6-Dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide or (3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide, Example 21.0

A 20 mL pressure vial was charged with Example 21.4 (107 mg, 0.192 mmol) and partially dissolved in IPA (959 μL) and water (959 μL). To that solution was added NaOH (1.0 N aqueous solution, 288 μL, 0.288 mmol), and the vial was sealed and placed into a reaction block preheated to 80° C. After 24 h, the RT solution was filtered through a 0.45 g syringe tip filter and purified by preparative HPLC: 50 u Silica Gel 19×100 mm+XSelect CSH Prep C18 10 u ODB 19×100 mm, A: Water 0.1% formic acid B: ACN 0.1% formic acid, Gradient: 25% (2 min), 25-75% (7 min), 95% (2 min), Flow Rate: 40 mL/min, 3 injection(s) monitored at 254 nm. The fractions containing product were concentrated on the speed vac overnight. Once dry, a water/ACN mixture was used to dissolve the product. The solution was subsequently frozen and lyophilized over night to give the title compound (29 mg, 0.054 mmol, 28% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (1H, s) 8.44-8.46 (2H, m) 7.29-7.52 (6H, m) 6.83 (2H, dd, J=8.50, 5.44 Hz) 4.94 (1H, br d, J=12.08 Hz) 4.55 (1H, br d, J=11.92 Hz) 3.72 (3H, s) 3.70 (3H, s) 2.66-2.93 (3H, m) 2.11 (1H, br d, J=10.73 Hz) 1.78 (1H, br d, J=13.16 Hz) 1.53-1.64 (1H, m) 1.37-1.48 (1H, m). LCMS-ESI (pos.) m/z: 540.2 (M+H)⁺.

Example 22.0. Preparation of (3S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide or (3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide

3S)—N-(4-(2,6-Dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide or (3R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3-piperidinesulfonamide, Example 22.0

The above title compound was synthesized following the procedure described for Example 21.0 using known starting materials as described: benzhydrazide (Acros Organics), 2-isothiocyanato-1,3-dimethoxybenzene (Example 1.2) and Example 21.2. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (3H, s) 8.44-8.46 (6H, m) 7.29-7.52 (21H, m) 6.83 (7H, dd, J=8.50, 5.44 Hz) 4.94 (3H, br d, J=12.08 Hz) 4.55 (4H, br d, J=11.92 Hz) 3.71 (20H, d, J=8.09 Hz) 3.38 (1H, s) 2.67-2.94 (12H, m) 2.61 (1H, br s) 2.34 (1H, t, J=1.79 Hz) 2.11 (3H, br d, J=10.73 Hz) 1.78 (3H, br d, J=13.16 Hz) 1.53-1.64 (3H, m) 1.37-1.48 (3H, m). LCMS-ESI (pos.) m/z: 540.2 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 4 Example Reagents Structure, Name and Data 23.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2- yl)propane-2-sulfonamide (Example 103.0), benzhydrazide (Acros Organics), 3-isothiocyanato- 2,4-dimethoxypyridine (Example 52.1). The racemic mixture was separated by preparative SFC method: Column: Chiralpak OZ-H 2 × 25 cm + OZ-H 2 × 15 cm, Mobile Phase: 75:35 (A:B) A: Liquid CO₂; B: MeOH, Flowrate: 60 mL/min, 239 nm, Inlet Pressure: 100 bar to deliver Example 23.0 as Peak 1.

 

(1R,2S,P)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide or (1R,2S,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.26 (1 H, s) 8.65 (2 H, s) 8.24 (1 H, d, J = 5.97 Hz) 7.38-7.49 (3 H, m) 7.32-7.37 (2 H, m) 6.99 (1 H, d, J = 5.97 Hz) 4.82 (1 H, d, J = 3.50 Hz) 3.80 (3 H, s) 3.78 (3 H, s) 3.42 (1 H, br dd, J = 6.94, 3.44 Hz) 3.16 (3 H, s) 2.27 (3 H, s) 1.14 (3 H, d, J = 7.01 Hz). LCMS-ESI (pos.) m/z: 526.2 (M + H)⁺. 24.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2- yl)propane-2-sulfonamide (Example 103.0), benzhydrazide (Acros Organics), 3-isothiocyanato- 2,4-dimethoxypyridine (Example 52.1). The racemic mixture was separated by preparative SFC method: Column: Chiralpak OZ-H 2 × 25 cm + OZ-H 2 × 15 cm, Mobile Phase: 75:35 (A:B) A: Liquid CO₂; B: MeOH, Flowrate: 60 mL/min, 239 nm, Inlet Pressure: 100 bar to deliver Example 24.0 as Peak 2.

 

(1R,2S,P)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide or (1R,2S,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.26 (1 H, s) 8.65 (2 H, s) 8.24 (1 H, d, J = 5.97 Hz) 7.38-7.49 (3 H, m) 7.32-7.37 (2 H, m) 6.99 (1 H, d, J = 6.10 Hz) 5.76 (1 H, s) 4.82 (1 H, d, J = 3.50 Hz) 3.82 (3 H, s) 3.76 (3 H, s) 3.42(1 H, br dd, J = 6.88, 3.37 Hz) 3.15 (3 H, s) 2.27 (3 H, s) 1.14 (3 H, d, J = 7.01 Hz). LCMS-ESI (pos.) m/z: 526.2 (M + H)⁺. 25.0 (2S,3R)-3-(5-methylpyrazin- 2-yl)butane-2-sulfonamide (Example 102.2), benzhydrazide (Acros Organics), 2-isothiocyanato- 1,3-dimethoxybenzene (Example 1.2).

(2S,3R)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2- butanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.19 (1 H, s) 8.44 (1 H, s) 8.32 (1 H, d, J = 1.17 Hz) 7.42-7.50 (2 H, m) 7.32-7.39 (4 H, m) 6.81 (2 H, dd, J = 8.63, 3.70 Hz) 3.68 (3 H, s) 3.68 (3 H, s) 3.53-3.62 (1 H, m) 2.43-2.46 (3 H, m) 1.23 (3 H, d, J = 7.14 Hz) 1.13 (3 H, d, J = 7.01 Hz). LCMS-ESI (pos.) m/z: 509.2 (M + H)⁺. 26.0 (2S,3R)-3-(5-methylpyrazin- 2-yl)butane-2-sulfonamide (Example 102.2), benzhydrazide (Acros Organics), 5-isothiocyanato- 4,6-dimethoxypyrimidine (Example 1.1).

(2S,3R)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5- phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.43 (1 H, s) 8.66 (1 H, s) 8.44 (1 H, s) 8.37 (1 H, s) 7.49-7.54 (1 H, m) 7.45 (2 H, t, J = 7.53 Hz) 7.38 (2 H, d, J = 7.24 Hz) 3.88 (6 H, s) 3.58 (1 H, br dd, J = 7.07, 3.70 Hz) 3.35- 3.41 (1 H, m) 2.44-2.46 (3 H, m) 1.24 (3 H, d, J = 7.14 Hz) 1.14 (3 H, d, J = 7.01 Hz). LCMS-ESI (pos.) m/z: 511.2 (M + H)⁺. 27.0 (S)-1-(5-fluoropyrimidin-2- yl)piperidine-3-sulfonamide or (R)-1-(5-fluoropyrimidin- 2-yl)piperidine-3- sulfonamide (Example 21.2), benzhydrazide (Acros Organics), 5-isothiocyanato- 4,6-dimethoxypyrimidine (Example 1.1).

(3S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl- 4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3- piperidinesulfonamide or (3R)-N-(4-(4,6-dimethoxy- 5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-3-piperidinesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (1 H, s) 8.67 (1 H, s) 8.44 (2 H, s) 7.31-7.51 (6 H, m) 4.93 (1 H, br d, J = 9.69 Hz) 4.54 (1 H, br d, J = 12.80 Hz) 3.90 (7 H, s) 2.80-2.90 (1 H, m) 2.10 (1 H, br d, J = 12.80 Hz) 1.79 (1 H, br d, J = 13.01 Hz) 1.54-1.66 (1 H, m) 1.36-1.51 (1 H, m). LCMS-ESI (pos.) m/z: 542.2 (M + H)⁺. 28.0 (S)-1-(5-fluoropyrimidin-2- yl)piperidine-3-sulfonamide or (R)-1-(5-fluoropyrimidin- 2-yl)piperidine-3- sulfonamide (Example 21.3), benzhydrazide (Acros Organics), 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

(3S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl- 4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-3- piperidinesulfonamide or (3R)-N-(4-(4,6-dimethoxy- 5-pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-3-piperidinesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (1 H, s) 8.67 (1 H, s) 8.44 (2 H, s) 7.31-7.51 (6 H, m) 4.93 (1 H, br d, J = 9.69 Hz) 4.54 (1 H, br d, J = 12.80 Hz) 3.90 (7 H, s) 2.80-2.90 (1 H, m) 2.10 (1 H, br d, J = 12.80 Hz) 1.79 (1 H, br d, J = 13.01 Hz) 1.54-1.66 (1 H, m) 1.36-1.51 (1 H, m). LCMS-ESI (pos.) m/z: 542.2 (M + H)⁺.

Example 29.0. Preparation of (S)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide or (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide

(S)-Piperidine-3-sulfonamide hydrochloride and (R)-piperidine-3-sulfonamide hydrochloride, Example 29.1

A solution of 4-chloropyridine-3-sulfonamide (5.0 g, 25.9 mmol) in AcOH (150 mL) was place in a Parr bottle. The solution was bubbled with nitrogen gas for 5 min. To this solution was added a suspension of platinum (IV) oxide (5.9 g, 25.9 mmol) in AcOH (30 mL). The reaction was stirred under hydrogen atmosphere (50 psi) for 72 h. The reaction mixture was filtered through a pad of Celite® filter aid, washing the Celite® filter aid pad with MeOH (2×50 mL). The combined filtrate was concentrated under reduced pressure to provide Example 29.1 (6.0 g) as an oil which was used in the next step without further purification. LCMS-ESI (pos.) m/z: 165.0 (M+H)⁺.

(S)-tert-Butyl 3-sulfamoylpiperidine-1-carboxylate and (R)-tert-butyl 3-sulfamoylpiperidine-1-carboxylate, Example 29.2

To a mixture of Example 29.1 (12.0 g, 59.8 mmol) and TEA (41.6 mL, 298.9 mmol) in DCM (215 mL) was added a solution of Boc anhydride (15.7 mL, 71.8 mmol) in DCM (70 mL) at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was then washed with water (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to obtain the material which was purified by column chromatography (silica: 100-200 mesh; elution: 0-30% EtOAc in DCM) to provide Example 29.2 (4.6 g, 34%, over two steps) as a white solid. ¹H NMR (400 MHz, CD₃CN) δ 5.30 (s, 2H), 4.36 (d, J=11.8 Hz, 1H), 3.94 (d, J=13.3 Hz, 1H), 3.01-2.84 (m, 2H), 2.64-2.58 (s, 1H), 2.20 (d, J=13.3 Hz, 1H), 1.78 (d, J=13.5 Hz, 1H), 1.74-1.57 (m, 2H), 1.43 (s, 9H). LCMS-ESI (neg.) m/z: 263 (M−H)⁻.

(S)-tert-Butyl 3-(N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)sulfamoyl)piperidine-1-carboxylate and (R)-tert-butyl 3-(N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl) sulfamoyl)piperidine-1-carboxylate, Example 29.3

The above title compound was synthesized following the procedure in Example 21.0 using known starting materials as described: benzhydrazide (Acros Organics), 5-isothiocyanato-4,6-dimethoxypyrimidine (Example 1.1) and (S)-tert-butyl 3-sulfamoylpiperidine-1-carboxylate and (R)-tert-butyl 3-sulfamoylpiperidine-1-carboxylate (Example 29.2). ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.37 (m, 10H) 1.45 (br d, J=10.88 Hz, 1H) 1.62-1.71 (m, 1H) 1.98-2.06 (m, 1H) 2.54 (br s, 2H) 2.87 (br s, 1H) 3.77-3.83 (m, 1H) 3.85 (s, 3H) 3.86 (s, 3H) 4.20 (br s, 1H) 7.31 (d, J=7.15 Hz, 2H) 7.39 (t, J=7.39 Hz, 2H) 7.43-7.49 (m, 1H) 8.61 (s, 1H) 13.47 (s, 1H). LCMS-ESI (POS.) m/z: 546 (M+H)⁺.

(S)—N-(4-(4,6-Dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide 2,2,2-trifluoroacetate and (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide 2,2,2-trifluoroacetate, Example 29.4

A 50 mL round bottom flask was charged with Example 29.3 (502 mg, 0.92 mmol) which was then dissolved in DCM (10 mL). To that solution was added TFA (6.1 g, 53.8 mmol, 4 mL). After 2.5 h, LCMS showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give Example 29.4 (410 mg, 100% yield). LCMS-ESI (pos.) m/z: 446.2 (M+H)⁺.

(S)—N-(4-(4,6-Dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide and (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide, Example 29.5

A 40 mL pressure vial was charged with Example 29.4 (71 mg, 0.16 mmol) which was then dissolved in DMSO (1.6 mL). To that solution was added 2-chloro-5-methylpyrimidine (83 μL, 0.80 mmol) followed by Hunig's base (277 μL, 1.59 mmol). The vial was sealed and placed into a reaction block preheated to 100° C. After 4 h, the reaction was cooled to RT and diluted with DCM and water. The contents of the vial were transferred into a separatory funnel and the layers were separated. The organic layer was washed with water (×3). The aqueous layer was analyzed for product and showed a large presence of product. The aqueous layer was re-extracted using 3:1 EtOAc/EtOH (×3). The combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced and purified by flash chromatography: Redi-Sep Rf Gold 12 g—CV=16.8 mL, eluting with EtOAc:EtOH 3:1 (v/v) in DCM 0% (2 CV), 0-40% (15 CV), 40% (5 CV) to provide Example 29.5 (54 mg, 0.10 mmol, 63% yield) as an orange solid. LCMS-ESI (pos.) m/z: 538.2 (M+H)⁺.

(S)—N-(4-(4,6-Dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide or (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide, Example 29.0

A chiral SFC purification of Example 29.5 was performed. Preparative SFC SFC method: Column: Chiralpak AS-H 2×15 cm, Mobile Phase: 50:50 (A:B) A: Liquid CO₂; B: IPA, Flowrate: 80 mL/min, 222 nm, Inlet Pressure: 100 bar to provide two peaks of >99.5% ee: The first eluting peak was assigned as Example 29.0. ¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (1H, s) 8.68 (1H, s) 8.22 (2H, d, J=0.62 Hz) 7.49-7.54 (1H, m) 7.42-7.48 (2H, m) 7.35-7.40 (2H, m) 4.94-5.00 (1H, m) 4.58 (1H, br d, J=11.45 Hz) 3.91 (3H, s) 3.89 (3H, s) 2.85-2.95 (1H, m) 2.73-2.81 (1H, m) 2.62-2.71 (1H, m) 2.13 (1H, br s) 2.08 (3H, s) 1.77 (1H, br d, J=13.16 Hz) 1.52-1.65 (1H, m) 1.35-1.47 (1H, m). LCMS-ESI (pos.) m/z: 538.2 (M+H)⁺. Peak assignment was determined by analytical SFC: Chiralpak AS-H.

Example 30.0. Preparation of (S)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide or (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide

(S)—N-(4-(4,6-Dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide or (R)—N-(4-(4,6-dimethoxypyrimidin-5-yl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-methylpyrimidin-2-yl)piperidine-3-sulfonamide, Example 30.0

The second eluting peak from the conditions described in Example 29.0 was assigned Example 30.0. ¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (1H, s) 8.68 (1H, s) 8.21 (2H, s) 7.51 (1H, d, J=7.15 Hz) 7.45 (2H, t, J=7.52 Hz) 7.35-7.40 (2H, m) 4.93-5.00 (1H, m) 4.54-4.62 (1H, m) 3.91 (3H, s) 3.89 (3H, s) 2.91 (1H, br s) 2.73-2.81 (1H, m) 2.63-2.71 (1H, m) 2.09-2.15 (1H, m) 2.08 (3H, s) 1.72-1.81 (1H, m) 1.51-1.66 (1H, m) 1.40 (1H, br d, J=12.13 Hz). LCMS-ESI (pos.) m/z: 538.2 (M+H)⁺. Peak assignment was determined by analytical SFC: Chiralpak AS-H, 40% IPA.

The compounds set forth in the following table were synthesized following the procedure in Example 29.0 using the known starting material as described.

TABLE 5 Example Reagents Structure, Name and Data 31.0 2,5-dichloropyrimidine (Synthonix), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), benzhydrazide (Acros Organics), (S)-tert-butyl 3- sulfamoylpiperidine-1- carboxylate and (R)-tert- butyl 3-sulfamoylpiperidine- 1-carboxylate (Example 29.2). The racemic mixture was separated by preparative SFC method: Column: Chiralpak AS-H 2 × 15 cm, Mobile Phase: 40:60 (A:B) A: Liquid CO₂; B: IPA, Flowrate: 60 mL/min, 220 nm, Inlet Pressure: 133 bar to deliver Example 31.0 as Peak 1.

 

(3S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-piperidinesulfonamide or (3R)-1-(5- chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3- piperidinesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (1 H, s) 8.68 (1 H, s) 8.41 (2 H, s) 7.49-7.55 (1 H, m) 7.45 (2 H, t, J = 7.44 Hz) 7.35-7.39 (2 H, m) 4.93 (1 H, br d, J = 11.04 Hz) 4.53 (1 H, br d, J = 13.16 Hz) 3.91 (3 H, s) 3.89 (3 H, s) 2.97 (1 H, br s) 2.90 (1 H, d, J = 12.28 Hz) 2.77 (1 H, s) 2.06-2.16 (1 H, m) 1.75-1.85 (1 H, m) 1.55-1.70 (1 H, m) 1.37- 1.54 (1 H, m). LCMS-ESI (pos.) m/z: 558.2 (M + H)⁺. 32.0 2,5-dichloropyrimidine (Synthonix), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), benzhydrazide (Acros Organics), (S)-tert-butyl 3- sulfamoylpiperidine-1- carboxylate and (R)-tert- butyl 3-sulfamoylpiperidine- 1-carboxylate (Example 29.2). The racemic mixture was separated by preparative SFC method: Column: Chiralpak AS-H 2 × 15 cm, Mobile Phase: 40:60 (A:B) A: Liquid CO₂; B: IPA, Flowrate: 60 mL/min, 220 nm, Inlet Pressure: 133 bar to deliver Example 32.0 as Peak 2.-

 

(3S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-piperidinesulfonamide or (3R)-1-(5- chloro-2-pyrimidinyl)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3- piperidinesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (1 H, s) 8.68 (1 H, s) 8.41 (2 H, s) 7.49-7.55 (1 H, m) 7.45 (2 H, t, J = 7.44 Hz) 7.35-7.39 (2 H, m) 4.93 (1 H, br d, J = 11.04 Hz) 4.53 (1 H, br d, J = 13.16 Hz) 3.91 (3 H, s) 3.89 (3 H, s) 2.97 (1 H, br s) 2.90 (1 H, d, J = 12.28 Hz) 2.77 (1 H, s) 2.06-2.16 (1 H, m) 1.75-1.85 (1 H, m) 1.55-1.70 (1 H, m) 1.37- 1.54 (1 H, m). LCMS-ESI (pos.) m/z: 558.2 (M + H)⁺.

Example 33.0. Preparation of (2S,3R)—N-(4-((1r,2R,6S)-2,6-dimethoxycyclohexyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide

(1R,2r,3S)-2-Nitrocyclohexane-1,3-diol, Example 33.1

A 500 mL round bottom flask was charged with glutaric dialdehyde (12.5 g, 50 mL, 25% aqueous solution, 125 mmol) and diluted with nitromethane (27.6 mL, 512 mmol) and a 1:1 solution of MeOH (69.3 mL) and water (69.3 mL). The solution was cooled to 0° C. and sodium carbonate (48.4 g, 457 mmol) in water (69.3 mL) was added. The resulting mixture was warmed to RT and stirred for 4 h. Carefully, AcOH (32.3 mL, 570 mmol) was added, and the solution was concentrated in vacuo to remove all volatile organics (bath temp 30-35° C.). Next, the water solution was partitioned with ether (5×200 mL), dried over sodium sulfate, filtered and concentrated to dryness. The material was then recrystallized with EtOAc to obtain the desired product (1R,2r,3S)-2-nitrocyclohexane-1,3-diol (7.5 g, 37%).

(1r,2R,6S)-2,6-Dimethoxycyclohexanamine, Example 33.2

Silver(I) oxide (6.15 mL, 192 mmol) was added to a DMF (96 mL) solution containing iodomethane (30.0 mL, 479 mmol) and (1R,2r,3S)-2-nitrocyclohexane-1,3-diol (7.72 g, 47.9 mmol). The resulting mixture was stirred overnight at RT. The reaction was then filtered and the filtrate was partitioned with EtOAc/water, washed with brine, dried over sodium sulfate, and concentrated. Next, the residue was dissolved in EtOH and Raney 2400 nickel (0.316 mL, 47.9 mmol) was added. The reaction was shaken in a Parr hydrogenator at 50 psi overnight. The reaction was then carefully filtered and concentrated in vacuo.

(1R,2r,3S)-2-Isothiocyanato-1,3-dimethoxycyclohexane, Example 33.3

1,1″-Thiocarbonyldi-2(1H)-pyridone (0.802 g, 3.45 mmol) was added to a DCM (15.70 mL) solution containing (1r,2R,6S)-2,6-dimethoxycyclohexanamine (0.5 g, 3.14 mmol). The resulting mixture was stirred overnight at RT. The reaction was concentrated and purified on silica eluting with a hexanes/EtOAc gradient (0-100%). Desired fractions were then pooled and concentrated to yield the desired compound (0.45 g, 71%).

(2S,3R)—N-(4-((1r,2R,6S)-2,6-Dimethoxycyclohexyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, Example 33.0

The above title compound was synthesized following the procedure in Example 21.0 using the starting materials (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide (Example 102.0), benzhydrazide (Acros Organics), and Example 33.3. ¹H NMR (500 MHz, DMSO-d₆) δ 13.06 (1H, s) 8.61 (2H, s) 7.62-7.66 (2H, m) 7.53-7.61 (3H, m) 4.18-4.26 (2H, m) 3.79-3.91 (1H, m) 3.60-3.73 (2H, m) 3.17 (3H, s) 3.15 (3H, s) 2.25 (3H, s) 2.17 (2H, br d, J=12.26 Hz) 1.64-1.74 (1H, m) 1.40 (3H, d, J=7.14 Hz) 1.27 (3H, d, J=7.07 Hz) 1.07-1.20 (1H, m) 0.89-1.00 (2H, m). LCMS-ESI (pos.) m/z: 515.2 (M+H)⁺.

Example 34.0. Preparation of (S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide or (R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide

(R)-tert-Butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)sulfamoyl)piperidine-1-carboxylate and (S)-tert-butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl) sulfamoyl)piperidine-1-carboxylate, Example 34.1

The above compounds were synthesized following the procedure described in the synthesis of Example 29.3 using 3-isothiocyanato-2,4-dimethoxypyridine (Example 1.2).

(R)-tert-Butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)sulfamoyl)piperidine-1-carboxylate or (S)-tert-butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl) sulfamoyl)piperidine-1-carboxylate, Example 34.2

A chiral SFC purification of racemic Example 34.1 was performed. Preparative SFC method: Column: Chiralpak AD-H 2×25 cm+Chiralpak AD-H 2×25 cm, Mobile Phase: 75:25 (A:B) A: Liquid CO₂; B: MeOH, Flowrate: 60 mL/min, 222 nm, Inlet Pressure: 100 bar to provide two peaks of >99.5% ee: The first eluting peak was assigned as Example 34.2. LCMS-ESI (pos.) m/z: 544.2 (M+H).

(R)-tert-Butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)sulfamoyl)piperidine-1-carboxylate or (S)-tert-butyl 3-(N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl) sulfamoyl)piperidine-1-carboxylate, Example 34.3

The second eluting peak from the conditions described in Example 34.2 was assigned Example 34.3. LCMS-ESI (pos.) m/z: 544.2 (M+H)⁺.

(S)-1-(5-Chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide or (R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide, Example 34.0

The above compound was synthesized following the procedure described in Example 29.5, using Example 34.3 and 2,5-dichloropyrimidine to give Example 34.0. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.32 (2H, s) 7.48 (1H, t, J=8.56 Hz) 7.40-7.44 (3H, m) 7.31-7.37 (2H, m) 6.70 (1H, s) 6.68 (1H, s) 5.03-5.11 (1H, m) 4.69 (1H, br d, J=12.85 Hz) 3.77 (3H, s) 3.76 (3H, s) 3.15 (1H, dd, J=12.98, 10.90 Hz) 3.05 (1H, tt, J=11.03, 3.70 Hz) 2.90-2.98 (1H, m) 2.29 (1H, br d, J=13.10 Hz) 1.76-1.97 (3H, m) 1.51-1.61 (1H, m). LCMS-ESI (pos.) m/z: 558.2 (M+H)⁺.

Example 35.0. Preparation of (S)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide or (R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide

(S)-1-(5-Chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide or (R)-1-(5-chloropyrimidin-2-yl)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)piperidine-3-sulfonamide, Example 35

The title compound was synthesized following the procedure described in Example 29.5, using 34.3 and 2,5-dichloropyrimidine to give Example 35.0. ¹H NMR (500 MHz, CD₂Cl₂) δ 8.30 (2H, s) 7.41-7.50 (4H, m) 7.31-7.36 (2H, m) 6.69 (2H, d, J=8.56 Hz) 5.04-5.09 (1H, m) 4.68 (1H, br d, J=13.23 Hz) 3.77 (7H, d, J=6.23 Hz) 3.10-3.15 (1H, m) 3.00-3.07 (1H, m) 2.88-2.95 (1H, m) 2.26-2.31 (1H, m) 1.87-1.95 (1H, m) 1.78-1.85 (1H, m) 1.49-1.59 (1H, m). LCMS-ESI (pos.) m/z: 558.2 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 6 36.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane-2- sulfonamide (Example 103.0), 3- isothiocyanato-2,4- dimethoxypyridine, Example 52.1., benzhydrazide (Commerically available from Frontier Scientific Services Inc.).

(1R,2S,P)-N-(4-(2,4-dimethoxy-3- pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)- 1-methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide and (1R,2S,S)-N-(4- (2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl- 2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ 1.33 (m, 3 H) 2.32 (s, 3 H) 3.30 (d, J = 3.01 Hz, 3 H) 3.63-3.72 (m, 1 H) 3.86 (m, 6 H) 4.94 (d, J = 4.15 Hz, 1 H) 6.70 (d, J = 5.96 Hz, 1 H) 7.33-7.40 (m, 2 H) 7.42-7.47 (m, 3 H) 8.21 (dd, J = 5.96, 1.61 Hz, 1 H) 8.61 (s, 2 H). LCMS (pos.) m/z: 526.2 (M + H)⁺.

Example 37.0. Preparation of 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

N-(2,6-Dimethoxyphenyl)-2-fluorobenzamide, Example 37.1

To an ice-cooled solution of 2,6-dimethoxyaniline (Amfinecom Inc., 1.0 g, 6.5 mmol) in DCM (22 mL) was added DIEA (2.28 mL, 13.1 mmol) via syringe followed by 2-fluorobenzoyl chloride (Fluka, 779 μL, 6.5 mmol) slowly via syringe. The resulting solution was stirred at 0° C. for 15 min and then was concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0-5% MeOH in DCM) to provide 37.1 (1.53 g, 85% yield) as a white solid. LCMS-ESI (pos.) m/z: 276.2 (M+H)⁺.

N-(2,6-Dimethoxyphenyl)-2-fluorobenzothioamide, Example 37.2

To a suspension of 37.1 (1.30 g, 4.7 mmol) in toluene (23.5 mL) was added Lawesson's reagent (1.15 g, 2.8 mmol). The resulting light yellow slurry was heated at reflux for 9.5 h and was then allowed to cool to RT and stirred for an additional 2 d. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-20% EtOAc in hexaness) to provide 37.2 (1.24 g, 90% yield) as a bright yellow solid. LCMS-ESI (pos.) m/z: 292.2 (M+H)⁺.

N-(2,6-Dimethoxyphenyl)-2-fluorobenzohydrazonamide, Example 37.3

To a solution of 37.2 (1.08 g, 3.7 mmol) in EtOH (12.4 mL) was added anhydrous hydrazine (1.16 mL, 37.1 mmol) via syringe. The resulting slurry was stirred at RT overnight, after which the reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL) and extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl ether to provide 37.3 (837 mg, 78% yield) as a tan solid. LCMS-ESI (pos.) m/z: 290.2 (M+H)⁺.

4-(2,6-Dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-amine, Example 37.4

To a slurry of 37.3 (430 mg, 1.49 mmol) in 1,4-dioxane (2.5 mL) and water (2.5 mL) was added sodium bicarbonate (131 mg, 1.57 mmol) followed by cyanogen bromide (5.0 M solution in ACN, 327 μL, 1.64 mmol) slowly via syringe. The reaction was stirred at RT for 2 h and then was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). The resulting mixture was extracted with DCM (3×) and the combined organic layers were washed with brine (1×), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 20-80% ACN in water over a 30 min period where both solvents contain 0.1% TFA). The purified product was partitioned between saturated aqueous sodium bicarbonate solution and DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide 37.4 (220 mg, 47% yield) as a white solid. LCMS-ESI (pos.) m/z: 315.2 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 37.4 using the known starting material as described.

TABLE 7 Ex- ample Reagents Structure, Name and Data 37.5 benzoyl chloride (Sigma-Aldrich).

4-(2,6-dimethoxyphenyl)-5-phenyl- 4H-1,2,4-triazol-3-amine. LCMS-ESI (pos.) m/z: 297.2 (M + H)⁺.

Example 37.0. Preparation of 2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

2-(4-Chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 37.0

To a solution of 37.4 (135 mg, 0.43 mmol) and TEA (299 μL, 2.15 mmol) in DCM (2.2 mL) was added 2-(4-chlorophenyl)ethanesulfonyl chloride (Synchem Inc., 205 mg, 0.86 mmol). The reaction was stirred at RT for 30 min and then was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). The mixture was extracted with DCM (3×) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase preparatory HPLC (Sunfire 5 μM C18 column, eluent: 40-80% ACN in water over a 30 min period where both solvents contain 0.1% TFA. The purified product was partitioned between saturated aqueous sodium bicarbonate solution and DCM (3×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford 37.0 (60.5 mg, 27% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.50 (m, 1H), 7.38 (t, J=8.5 Hz, 1H), 7.26-7.35 (m, 3H), 7.08-7.22 (m, 4H), 6.68 (d, J=8.6 Hz, 2H), 3.71 (s, 3H), 3.71 (s, 3H), 3.24-3.31 (m, 2H), 3.01-3.07 (m, 2H). LCMS-ESI (pos.) m/z: 517.2 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 37.0 using the starting material as described.

TABLE 8 Example Reagents Structure, Name and Data 38.0 4-(2,6-dimethoxyphenyl)-5- phenyl-4H-1,2,4-triazol-3- amine (Example 37.5).

2-(4-chlorophenyl)-N-(4-(2,6-dimethoxyphenyl)-5- phenyl-4H-1,2,4-triazol-3-yl)ethanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 10.90 (br. s, 1H), 7.35- 7.42 (m, 3H), 7.24-7.32 (m, 5H), 7.11 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 3.69 (s, 3H), 3.69 (s, 3H), 3.23-3.30 (m, 2H), 3.06-3.12 (m, 2H). LCMS- ESI (pos.) m/z: 499.2 (M + H)⁺.

Example 39.1. Preparation of 2,2-difluorobenzo[d][1,3]dioxole-5-carbohydrazide

2,2-Difluorobenzo[d][1,3]dioxole-5-carbohydrazide, Example 39.1

To a stirred solution of methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate (1.0 g, 4.63 mmol) in MeOH (20 mL) at 0° C. was added hydrazine hydrate solution (0.277 mL, 6.94 mmol). The reaction mixture was stirred at RT for 18 hrs. LC-MS showed product and some starting material. Thus, more hydrazine hydrate solution (0.1 mL) was added and the mixture was stirred at RT. After 2 days, LC-MS showed that starting material was still present. More hydrazine hydrate solution (0.277 mL, 6.94 mmol) was added, and the reaction mixture was stirred for 3 days. LC-MS then showed that the reaction was complete. The reaction mixture was concentrated. The initial product was washed with water, filtered and dried under vacuo to give 2,2-difluorobenzo[d][1,3]dioxole-5-carbohydrazide (1.0 g, 4.63 mmol, 100% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.50-7.60 (m, 2H), 7.13 (d, J=8.07 Hz, 1H).

The compounds set forth in the following table were synthesized following the procedure in Example 1.0 using the known starting material as described.

TABLE 9 Example Reagents Structure, Name and Data 39.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane- 2-sulfonamide (Example 103.0), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2), 2,2- difluorobenzo[d][1,3]dioxole-5- carbohydrazide (Example 39.1).

(1R,2S)-N-(5-(2,2-difluoro-1,3-benzodioxol-5-yl)-4- (2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, CDCl₃) δ 11.13 (br. s., 1 H), 8.53 (s, 2 H), 7.32 (t, J = 8.56 Hz, 1 H), 7.05-7.12 (m, 2 H), 6.90 (d, J = 8.56 Hz, 1 H), 6.55 (d, J = 8.56 Hz, 2 H), 4.89 (d, J = 4.65 Hz, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.63-3.66 (m, 1 H), 3.26 (s, 3 H), 2.25 (s, 3 H), 1.30 (d, J = 7.09 Hz, 3 H). LCMS-ESI (pos.) m/z: 605.0 (M + H)⁺. 50.0 (2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide (Example 102.0), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), 3-cyanobenzohydrazide (Frontier Scientific Services).

(2S,3R)-N-(5-(3-cyanophenyl)-4-(4,6-dimethoxy-5- pyrimidinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.59 (br s, 1 H) 8.54 (d, J = 0.73 Hz, 2 H) 8.49 (s, 1 H) 7.71-7.79 (m, 2 H) 7.60 (dt, J = 8.19, 1.40 Hz, 1 H) 7.46-7.54 (m, 1 H) 3.97 (s, 3 H) 3.92 (s, 3 H) 3.90 (d, J = 6.95 Hz, 1 H) 3.73 (quin, J = 6.84 Hz, 1 H) 2.30 (s,3 H) 1.40 (app t, J = 7.36 Hz, 6 H). LCMS-ESI (pos.) m/z: 536.2 (M + H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 10 Example Reagents Structure, Name and Data 40.0 (2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide (Example 102.0), 1,3-difluoro- 2-isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(2S,3R)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2- butanesulfonamide ¹H NMR (400 MHz, CDCl₃) δ 11.49 (br s, 1 H) 8.54 (d, J = 0.62 Hz, 2 H) 7.30-7.56 (m, 6 H) 7.04 (td, J = 9.87, 8.55 Hz, 2 H) 3.92 (quin, J = 6.76 Hz, 1 H) 3.75 (quin, J = 6.87 Hz, 1 H) 2.30 (s, 3 H) 1.41 (d, J = 2.49 Hz, 3 H) 1.39 (d, J = 2.59 Hz, 3 H). LCMS-ESI (pos.) m/z: 485.2 (M + H)⁺. 41.0 (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propane- 2-sulfonamide (Example 103.0), 1,3-difluoro-2- isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(1R,2S)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2- pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.27 (br s, 1 H) 8.63 (s, 2 H) 7.43-7.51 (m, 2 H) 7.33-7.43 (m, 4 H) 7.05 (td, J = 8.50, 5.18 Hz, 2 H) 5.00 (d, J = 4.56 Hz, 1 H) 3.75-3.80 (m, 1 H) 3.36 (s, 3 H) 2.34 (s, 3 H) 1.41 (d, J = 7.05 Hz, 3 H). LCMS-ESI (pos.) m/z: 501.2 (M + H)⁺. 42.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2-yl)propane- 2-sulfonamide (Example 104.0), 1,3-difluoro-2- isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(1S,2S)-N-(4-(2,6-difluorophenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-1-(1-methylethoxy)-1-(5-methyl-2- pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 13.22 (s, 1 H) 8.66 (d, J = 0.62 Hz, 2 H) 7.28-7.57 (m, 6 H) 7.04-7.12 (m, 1 H) 6.94-7.01 (m, 1 H) 4.89 (d, J = 3.32 Hz, 1 H) 3.76 (qd, J = 7.19, 2.90 Hz, 1 H) 3.58 (quin, J = 6.01 Hz, 1 H) 2.33-2.45 (m, 3 H) 1.58 (d, J = 7.05 Hz, 3 H) 1.12 (d, J = 6.01 Hz, 3 H) 1.00 (d, J = 6.22 Hz, 3 H). LCMS- ESI (pos.) m/z: 529.2 (M + H)⁺. 43.0 (2S,3R)-3-(5-methylpyrazin-2- yl)butane-2-sulfonamide (Example 102.2), 1,3-difluoro- 2-isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(5- (cyclopentylmethyl)-4-(4,6-dimethoxy-5- pyrimidinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-2- propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.33-8.39 (m, 2 H) 7.30-7.57 (m, 6 H) 7.05 (ft, J = 8.68, 1.37 Hz, 2 H) 3.77 (qd, J = 7.05, 4.35 Hz, 1 H) 3.59 (qd, J = 7.01, 4.25 Hz, 1 H) 2.53 (s, 3 H) 1.38 (s, 3H) 1.38 (s, 3H). LCMS-ESI (pos.) m/z: 485.2 (M + H)⁺. 44.0 (1R,2S)-1-((tert- butyldimethylsilyl)oxy)-1-(5- methylpyrimidin-2-yl)propane- 2-sulfonamide (Example 113.0), 1,3-difluoro-2- isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(1R,2S)-1-((tert-butyl(dimethyl)silyl)oxy)-N-(4-(2,6- difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.68 (br s, 1 H) 8.60 (d, J = 0.83 Hz, 2 H) 7.34-7.54 (m, 6 H) 7.01-7.11 (m, 2 H) 5.20 (d, J = 7.46 Hz, 1 H) 3.92 (quin, J = 7.10 Hz, 1 H) 2.33 (s, 3 H) 1.56 (d, J = 7.05 Hz, 3 H) 0.84 (s, 9 H) 0.07 (s, 3 H) −0.15 (s, 3 H). LCMS-ESI (pos.) m/z: 601.2 (M + H)⁺. 45.0 (1R,2S)-1-((tert- butyldimethylsilyl)oxy)-1-(5- methylpyrimidin-2-yl)propane- 2-sulfonamide (Example 113.0), 1,3-difluoro-2- isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros). The silyl protecting group was removed in situ during base mediated cyclodehydration step.

46.0 (2S,3R)-3-(5-chloropyrimidin- 2-yl)butane-2-sulfonamide (Example 102.4), 1,3-difluoro- 2-isothiocyanatobenzene (Sigma Aldrich), benzhydrazide (Acros).

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(4-(2,6- difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2- butanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.12 (br s, 1 H) 8.64 (s, 2 H) 7.44-7.55 (m, 2 H) 7.32-7.43 (m, 4 H) 7.00- 7.11 (m, 2 H) 3.91 (quin, J = 6.82 Hz, 1 H) 3.79 (quin, J = 6.87 Hz, 1H) 1.41 (d, J = 4.25 Hz, 3 H) 1.39 (d, J = 4.46 Hz, 3 H) 1.37-1.40 (m, 1H). LCMS-ESI (pos.) m/z: 505.0 (M + H)⁺. 48.0 (2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide (Example 102.0), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), 3- (trifluoromethyl)benzhydrazide (Frontier Scientific Services).

(2S,3R)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(3- (trifluoromethyflphenyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.52 (br s, 1 H) 8.54 (d, J = 0.62 Hz, 2 H) 8.47 (s, 1 H) 7.67-7.76 (m, 2 H) 7.55-7.60 (m, 1 H) 7.48-7.54 (m, 1 H) 3.95 (s, 3 H) 3.91-3.94 (m, 1 H) 3.91 (s, 3 H) 3.74 (quin, J = 6.92 Hz, 1 H) 2.30 (s, 3 H) 1.42 (s, 3 H) 1.35-1.40 (m, 3 H). LCMS-ESI (pos.) m/z: 579.2 (M + H)⁺. 49.0 (2S,3R)-3-(5-methylpyrazin-2- yl)butane-2-sulfonamide (Example 102.2), 5- isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), 3- (trifluoromethyl)benzhydrazide (Frontier Scientific Services).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(4,6- dimethoxy-5-pyrimidinyl)-5-(2-methylpropyl)-4H- 1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.03 (s, 1 H) 8.48 (s, 1 H) 8.38 (s, 2 H) 7.67-7.77 (m, 2 H) 7.55-7.62 (m, 1 H) 7.47-7.55 (m, 1 H) 3.94 (s, 3 H) 3.93 (s, 3 H) 3.77 (dd, J = 7.10, 4.20 Hz, 1 H) 3.61 (dd, J = 7.00, 4.41 Hz, 1 H) 2.55 (s, 3 H) 1.40 (d, J = 7.15 Hz, 3 H) 1.37 (d, J = 7.05 Hz, 3 H). LCMS-ESI (pos.) m/z: 579.2 (M + H)⁺.

The compound set forth in the following table was synthesized following the procedure in Example 112.2 using methanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (X-Phos Palladacycle Generation 3) in place of bis-(tri-tert-butylphosphine)palladium and Example 46.0.

TABLE 11 Example Reagents Structure, Name and Data 47.0 (2S,3R)-3-(5-chloro-2- pyrimidinyl)-N-(4-(2,6- difluorophenyl)-5-phenyl-4H- 1,2,4-triazol-3-yl)-2- butanesulfonamide (Example 46.0).

(2S,3R)-3-(5-cyano-2-pyrimidinyl)-N-(4-(2,6- difluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2- butanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 11.00 (br s, 1 H) 8.94 (s, 2 H) 7.44-7.57 (m, 2 H) 7.33-7.44 (m, 4 H) 7.03- 7.13 (m, 2 H) 3.91-4.00 (m, 1 H) 3.81 (quin, J = 7.10 Hz, 1 H) 1.44 (d, J = 6.95 Hz, 3 H) 1.41 (d, J = 7.05 Hz, 3 H). LCMS-ESI (pos.) m/z: 496.2 (M + H)⁺.

Example 51.0. Preparation of 2-(4-chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide

N-(2-(Trifluoromethyl)phenyl)benzamide, Example 51.1

To a 500-mL round-bottomed flask was added 3-(trifluoro-o-tolyl) isocyanate (Sigma-Aldrich Chemical Company, Inc., 5.06 g, 26.2 mmol) in THF (100 mL). The solution was cooled to −78° C. and phenylmagnesium bromide (3.0 M solution in diethyl ether, Sigma-Aldrich Chemical Company, Inc., 9.62 mL, 28.9 mmol) was added dropwise via syringe with stirring. The reaction mixture was then stirred at −78 to 0° C. for 2 h. LCMS analysis indicated the reaction was complete. The reaction mixture was then diluted with saturated NH₄Cl at 0° C. and extracted with DCM. The combined organic layers were washed with 10% Na₂CO₃ and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give the material as a light-yellow oil. The material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 10% to 40% EtOAc in hexanes, to provide the title compound Example 51.1 (3.68 g, 13.9 mmol, 53% yield) as a white solid. LCMS-ESI (pos.), m/z: 266.0 (M+H)⁺.

N-(2-(Trifluoromethyl)phenyl)benzohydrazonamide, Example 51.2

To a 500-mL round-bottomed flask was added Example 51.1 (3.68 g, 13.87 mmol) and thionyl chloride (30.4 mL, 416 mmol). The reaction mixture was stirred at 70° C. for 20 h. The reaction solution was therein concentrated in vacuo to give the product as a light-yellow oil which was used directly in the next step without purification. To a 250-mL round-bottomed flask was added hydrazine, (anhydrous, 6.09 mL, 194 mmol) in benzene (19.39 mL). At 0° C., a mixture of (Z)—N-(2-(trifluoromethyl)phenyl)benzimidoyl chloride (2.2 g, 7.76 mmol) in benzene (19.4 mL) was added to this solution dropwise. The reaction mixture was then stirred at 0° C. to RT for 20 h. The reaction mixture was diluted with water and extracted with Et₂O. The organic extract was washed with saturated NaHCO₃ and brine, and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give the title compound (2.2 g, 7.88 mmol, 100% yield) as a tan oil. The product thus obtained was used directly in the next step without further purification. LCMS-ESI (pos.), m/z: 280.0 (M+H)⁺.

5-Phenyl-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-amine, Example 51.3

To a 250-mL round-bottomed flask was added Example 51.2 (1.22 g, 4.37 mmol) and cyanogen bromide (0.874 mL, 4.37 mmol) in MeOH (19.86 mL). The reaction mixture was stirred at 86° C. for 60 h. LCMS analysis indicated the reaction was complete. The product was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g, gold), eluting with a gradient of 60% to 100% EtOAc in DCM, to provide the title compound (0.786 g, 2.58 mmol, 59% yield) as a white powder. LCMS-ESI (pos.), m/z: 305.0 (M+H)⁺.

2-(4-Chlorophenyl)-N-(5-cyclopentyl-4-(2,6-dibromophenyl)-4H-1,2,4-triazol-3-yl)ethanesulfonamide, Example 51.0

To a 10-mL vial was added Example 51.3 (57.8 mg, 0.190 mmol) and TEA (53.0 μL, 0.380 mmol) in DCM (1.9 mL). 2-(4-Chlorophenyl)ethanesulfonyl chloride (50 mg, 0.209 mmol) was then added with stirring at RT. The reaction mixture was stirred at RT for 3 days. LCMS indicated that the desired product was formed. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with saturated NaCl and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give the product as a light-yellow solid. The product was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 0% to 40% EtOAc in DCM to provide the title compound (45 mg, 0.089 mmol, 47% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.61-7.79 (m, 3H) 7.40 (d, J=7.83 Hz, 1H) 7.32 (t, J=6.21 Hz, 1H) 7.15-7.26 (m, 6H) 7.01 (d, J=7.82 Hz, 2H) 3.08-3.24 (m, 2H) 2.92-3.02 (m, 2H). LCMS-ESI (pos.), m/z: 507.0 (M+H)⁺.

Example 52.0. Preparation of (2S,3R, P)—N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide and (2S,3R,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide

3-Isothiocyanato-2,4-dimethoxypyridine, Example 52.1

A 2 L round bottom flask was charged with 1,1″-thiocarbonyldi-2(1H)-pyridone (47.0 g, 202 mmol) and dissolved in dry DCM (405 mL). To that solution was added 2,6-dimethoxyaniline (31 g, 202 mmol) dissolved in DCM (405 mL) via an addition funnel at RT over 40 min. After 16 h, the reaction was concentrated in vacuo and purified on silica gel (0-20% EtOAc in heptanes) to give Example 52.1 (32 g, 164 mmol, 81% yield). LCMS-ESI (pos.) m/z: 197.1 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 1.0 using the known starting material as described and employing neat AcOH instead of methanesulfonic acid and dioxane.

TABLE 12 Example Reagents Structure, Name and Data 52.0 (2S,3R)-3-(5- methylpyrazin-2- yl)butane-2-sulfonamide (Example 102.2), 3- isothiocyanato-2,4- dimethoxypyridine, (Example 52.1), benzhydrazide (Acros).

(2S,3R,P)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide and (2S,3R,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J = 5.18 Hz, 1 H) 8.41 (d, J = 0.83 Hz, 1/2 H) 8.32 (d, J = 0.93 Hz, 1/2 H) 8.18 (dd, J = 5.96, 4.20 Hz, 1 H) 7.35-7.47 (m, 3 H) 7.28-7.35 (m, 2 H) 6.63 (dd, J = 10.94, 6.06 Hz, 1 H) 3.86 (app d, J = 5.60 Hz, 3 H) 3.78 (app d, J = 3.42 Hz, 3 H) 3.53-3.76 (m, 2 H) 2.61 (d, J = 1.55 Hz, 3 H) 1.34-1.43 (m, 6 H). LCMS-ESI (pos.) m/z: 510.2 (M + H)⁺.

Example 53.0. Preparation of (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide and (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3-piperidinesulfonamide

5-Hydroxypyridine-3-sulfonamide, Example 53.1

To a 100-mL round-bottomed flask was added 5-bromopyridine-3-sulfonamide (commercially available from Enamine, Kiev, Ukraine) (0.486 g, 2.05 mmol), 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-isopropylbiphenyl (commercially available from Strem Chemicals, Inc., MA, USA, 0.079 g, 0.16 mmol) and Pd₂(dba)₃ (Sigma-Aldrich Chemical Company, Inc., 0.038 g, 0.041 mmol). The flask was placed under vacuum and back-filled with a potassium hydroxide (0.345 g, 6.15 mmol) solution in dioxane (5 mL) and water (5 mL). The reaction mixture was then stirred at 100° C. under N₂ for 17 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to RT. The reaction mixture was diluted with 1 N HCl and washed with Et₂O. The aqueous phase was concentrated in vacuo to afford the title compound 53.1 (0.387 g, 2.22 mmol, 100% yield) as a white solid, which was used directly in the next step without further purification. LCMS-ESI (pos.), m/z: 175.1 (M+H)⁺.

(3R,5R)-5-Hydroxypiperidine-3-sulfonamide acetate and (3S,5R)-5-hydroxypiperidine-3-sulfonamide acetate and (3R,5S)-5-hydroxypiperidine-3-sulfonamide acetate and (3S,5S)-5-hydroxypiperidine-3-sulfonamide acetate, Example 53.2

To a 1 L hydrogenation flask was added 53.1 (6.46 g, 37.1 mmol) and AcOH (250 mL). Water (20 mL) was added as a co-solvent. The mixture was bubbled with N₂ for 2 min before platinum (iv) oxide hydrate (8.42 g, 37.1 mmol) was added under N₂. The flask was set up on a Parr shaker, vacuumed, and back-filled with N₂ two times, and then placed under vacuum and back-filled with hydrogen gas. The reaction mixture was stirred at RT under 50 psi of hydrogen gas for 24 h. LCMS analysis indicated that the reaction was complete. Celite® brand filter agent (20 g) was added to the mixture with stirring. The solid was removed by filtration after 10 min of stirring. The filter cake was rinsed with MeOH. The combined organic layers were concentrated in vacuo to afford 53.2 (8.91 g, 100% yield) as a light-yellow oil, which was directly used in the next step without purification. LCMS-ESI (pos.), m/z: 181.1 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and (3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide and (3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-hydroxypiperidine-3-sulfonamide, Example 53.3

To a 500 mL round-bottomed flask was added 53.2 (8.91 g, 37.1 mmol) and Hunig's base (32.3 mL, 185 mmol) in DMF (80 mL). 2-Chloro-5-fluoro-pyrimidine (18.32 mL, 148 mmol) was then added. The reaction mixture was stirred at 120° C. for 18 h. LCMS analysis indicated the reaction was complete. The reaction mixture was allowed to cool to RT and then was diluted with water and extracted with DCM. The organic layers were washed with brine and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give the initial material as an orange oil. The material thus obtained was purified by silica gel chromatography (a gradient of 0-100% EtOAc in DCM), to provide 53.3 (3.7 g, 10.93 mmol, 36% yield) as a light-yellow solid. LCMS-ESI (pos.), m/z: 277.0 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 13 Example Reagents Structure, Name and Data 53.0 (3S,5S)-1-(5- fluoropyrimidin-2-yl)-5- hydroxypiperidine-3- sulfonamide and (3S,5R)- 1-(5-fluoropyrimidin-2-yl)- 5-hydroxypiperidine-3- sulfonamide and (3R,5S)- 1-(5-fluoropyrimidin-2-yl)- 5-hydroxypiperidine-3- sulfonamide and (3R,5R)- 1-(5-fluoropyrimidin-2-yl)- 5-hydroxypiperidine-3- sulfonamide, Example 53.3, 3,3- dimethylbutanehydrazide (Enamine), 2- isothiocyanato-1,3- dimethoxybenzene (Example 1.2), benzhydrazide (Acros).

 

(3R,5S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3- piperidinesulfonamide and (3S,5R)-N-(4-(2,6-dimethoxyphenyl)- 5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5- hydroxy-3-piperidinesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ 10.96-11.26 (br s, 1 H) 8.24 (d, J = 0.62 Hz, 2 H) 7.38-7.52 (m, 4 H) 7.29-7.38 (m, 2 H) 6.69 (dq, J = 8.59, 0.94 Hz, 2 H) 4.81-4.93 (m, 1 H) 4.58-4.70 (m, 1 H) 3.79 (s, 3 H) 3.77 (s, 3 H) 3.66-3.76 (m, 1 H) 3.17-3.27 (m, 1 H) 3.05-3.17 (m, 1 H) 2.86 (dd, J = 12.75, 9.64 Hz, 1 H) 2.45- 2.56 (m, 1 H) 1.82 (ddd, J = 12.44, 11.09, 10.06 Hz, 1 H). LCMS- ESI (pos.) m/z: 556.2 (M + H)⁺. 54.0 The first peak of the SFC chiral separation of Example 52.0 under the following condition: SFC: Chiralcel OZ-H, 30% MeOH.

(2S,3R,P)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide or (2S,3R,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.38 (d, J = 1.04 Hz, 1 H) 8.34 (d, J = 1.45 Hz, 1 H) 8.21 (d, J = 5.91 Hz, 1 H) 7.39-7.50 (m, 3 H) 7.32-7.39 (m, 2 H) 6.68 (d, J = 6.01 Hz, 1 H) 3.86 (s, 3 H) 3.82 (s, 3 H) 3.65-3.75 (m, 1 H) 3.01 (q, J = 6.95 Hz, 1 H) 2.53 (s, 3 H) 1.37 (d, J = 7.15 Hz, 3 H) 1.32 (d, J = 7.05 Hz, 3 H). LCMS- ESI (pos.) m/z: 510.2 (M + H)⁺. 55.0 The second peak of the SFC chiral separation of Example 52.0 under the following condition: SFC: Chiralcel OZ-H, 30% MeOH.

(2S,3R,P)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide or (2S,3R,M)-N-(4-(2,4-dimethoxy-3-pyridinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-3-(5-methyl-2-pyrazinyl)-2-butanesulfonamide. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.38 (d, J = 0.93 Hz, 1 H) 8.33 (d, J = 1.45 Hz, 1 H) 8.21 (d, J = 6.01 Hz, 1 H) 7.39-7.49 (m, 3 H) 7.31-7.39 (m, 2 H) 6.69 (d, J = 5.91 Hz, 1 H) 3.87 (s, 3 H) 3.81 (s, 3 H) 3.65-3.76 (m, 1 H) 3.01 (q, J = 7.26 Hz, 1 H) 2.52 (s, 3 H) 1.36 (d, J = 7.15 Hz, 3 H) 1.31 (d, J = 7.05 Hz, 3 H). LCMS- ESI (pos.) m/z: 510.0 (M + H)⁺. 56.0 The first peak of the SFC chiral separation of Example 53.0 under the following condition: SFC: Chiralpak AS-H, 35% MeOH.

(3R,5S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3- piperidinesulfonamide or (3S,5R)-N-(4-(2,6-dimethoxyphenyl)- 5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5- hydroxy-3-piperidinesulfonamide. ¹H NMR (400 MHz, CD₃OD) δ 6.75 (d, J = 0.62 Hz, 2 H) 5.86- 5.99 (m, 4 H) 5.76-5.84 (m, 2 H) 5.21-5.28 (m, 2 H) 3.52- 3.62 (m, 1 H) 3.26-3.33 (m, 1 H) 2.25 (s, 3 H) 2.24 (s, 3 H) 2.00- 2.13 (m, 1 H) 1.80 (dt, J = 3.29, 1.62 Hz, 2 H) 1.51-1.64 (m, 1 H) 1.34 (dd, J = 12.85, 11.40 Hz, 1 H) 1.01 (dd, J = 12.59, 10.63 Hz, 2 H) 0.08-0.21 (m, 1 H). LCMS-ESI (pos.) m/z: 556.1 (M + H)⁺. 57.0 The second peak of the SFC chiral separation of Example 53.0 under the following condition: SFC: Chiralpak AS-H, 35% MeOH.

(3R,5S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-hydroxy-3- piperidinesulfonamide or (3S,5R)-N-(4-(2,6-dimethoxyphenyl)- 5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5- hydroxy-3-piperidinesulfonamide. ¹H NMR (400 MHz, CD₃OD) δ 6.75 (d, J = 0.73 Hz, 2 H) 5.86- 5.99 (m, 4 H) 5.76-5.83 (m, 2 H) 5.22-5.28 (m, 2 H) 3.53- 3.61 (m, 1 H) 3.26-3.32 (m, 1 H) 2.26 (s, 3 H) 2.24 (s, 3 H) 2.01- 2.12 (m, 1 H) 1.80 (dt, J = 3.24, 1.65 Hz, 2 H) 1.52-1.62 (m, 1 H) 1.34 (dd, J = 12.91, 11.35 Hz, 1 H) 0.94-1.05 (m, 2 H) 0.08- 0.19 (m, 1 H). LCMS-ESI (pos.) m/z: 556.1 (M + H)⁺.

Example 58.0. Preparation of (3R,5S)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide or (3S,5R)—N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide

5-Isopropoxypyridine-3-sulfonamide, Example 58.1

To a suspension of Example 53.1 (1.1 g, 6.32 mmol) in THF (16 mL) and IPA (16 mL) was added triphenylphosphine (1.99 g, 7.58 mmol). The mixture was bubbled with argon for 3 min before diisopropyl azodicarboxylate (1.49 mL, 7.58 mmol) was added dropwise at 0° C. under a N₂ stream. The reaction was then stirred at 0° C. to RT for 15 h. The reaction mixture was then concentrated in vacuo. The product was absorbed onto a plug of silica gel and purified by chromatography through a RediSep-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in heptanes, to provide the product fractions, which were combined and extracted with 1N HCl. The product was further purified by washing with acidic aqueous solution, which was then modified by saturated aqueous NaHCO₃ to pH>8. The basic aqueous solution was then extracted with DCM. The organic extract was washed with brine and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give Example 58.1 (0.95 g, 70% yield) as white solid. LCMS-ESI (pos.), m/z: 217.2 (M+H)⁺.

(3S,5R)-5-Isopropoxypiperidine-3-sulfonamide and (3R,5R)-5-isopropoxypiperidine-3-sulfonamide and (3S,5S)-5-isopropoxypiperidine-3-sulfonamide and (3R,5S)-5-isopropoxypiperidine-3-sulfonamide, Example 58.2

A solution of Example 58.1, 5-isopropoxypyridine-3-sulfonamide (1.8 g, 8.32 mmol) in AcOH (41.6 mL) was bubbled with argon gas for 2 min before platinum (IV) oxide (1.89 g, 8.32 mmol) was added under an argon stream. The above reaction mixture was then stirred at RT under 45 psi of hydrogen gas for two days. Next, Celite® filter aid (5 g) was added to the reaction mixture and the mixture was stirred at RT for 10 min. The mixture was then filtered and the solution was concentrated in vacuo to provide Example 58.2 as a light yellow oil, which was used in the next step without further purification. LCMS-ESI (pos.), m/z: 223.3 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide and (3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide and (3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide and (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide, Example 58.3

To a 40 mL vial (with pressure release septa) was added Example 58.2 (2 g, 4.96 mmol) and 2-chloro-5-fluoropyrimidine (3.29 g, 24.79 mmol). The reaction mixture was stirred at 90° C. for 21 h. LCMS indicated the reaction was complete. The reaction mixture was then concentrated in vacuo. The product thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a RediSep-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EOAc in heptanes, to provide Example 58.3, as a mixture of diastereomers (0.5 g, 1.6 mmol, 32% yield) as an off-white solid. LCMS-ESI (pos.), m/z: 319.2 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide or (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide, Example 58.4

Example 58.3 was separated by SFC on a Chiralpak AS-H column using 15% MeOH/CO₂. Examples 58.4 and 58.5 are a pair of enantiomers, 58.4 was the second peak among 4 isomers (earlier peak vs. its opposite enantiomer) on AS-H column. ¹H NMR (400 MHz, CD₃OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97 (dd, J=14.33, 1.58 Hz, 1H) 3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35 (m, 1H) 3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz, 1H) 8.27 (d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide or (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide, Example 58.5

Further elution under the conditions described in Example 58.4 gave 58.5 as the third peak. ¹H NMR (400 MHz, CD₃OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97 (dd, J=14.33, 1.58 Hz, 1H) 3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35 (m, 1H) 3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz, 1H) 8.27 (d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide or (3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide, Example 58.6

Examples 58.6 and 58.7 are a pair of enantiomers, 58.6 was the first peak among 4 isomers (earlier peak vs. its opposite enantiomer) on AS-H column under conditions described in Example 58.4. ¹H NMR (400 MHz, CD₃OD) δ 0.92 (d, J=6.12 Hz, 3H) 1.08 (d, J=6.01 Hz, 3H) 1.98 (ddd, J=13.19, 12.15, 2.95 Hz, 1H) 2.33 (m, 1H) 3.01 (dd, J=14.10, 1.66 Hz, 1H) 3.13 (dd, J=13.06, 10.99 Hz, 1H) 3.33-3.45 (m, 1H) 3.74 (dt, J=12.13, 6.06 Hz, 1H) 3.86-3.93 (m, 1H) 4.77-4.83 (m, 1H) 5.11 (m, 1H) 8.27 (d, J=0.62 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide or (3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-isopropoxypiperidine-3-sulfonamide, Example 58.7

Further elution under the conditions described in Example 58.4 gave 58.7 as the fourth peak. ¹H NMR (400 MHz, CD₃OD) δ 0.92 (d, J=6.12 Hz, 3H) 1.08 (d, J=6.01 Hz, 3H) 1.98 (ddd, J=13.19, 12.15, 2.95 Hz, 1H) 2.33 (m, 1H) 3.01 (dd, J=14.10, 1.66 Hz, 1H) 3.13 (dd, J=13.06, 10.99 Hz, 1H) 3.33-3.45 (m, 1H) 3.74 (dt, J=12.13, 6.06 Hz, 1H) 3.86-3.93 (m, 1H) 4.77-4.83 (m, 1H) 5.11 (m, 1H) 8.27 (d, J=0.62 Hz, 2H). LCMS-ESI (pos.) m/z: 319.2 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 14 Example Reagents Structure, Name and Data 58.0 (3S,5R)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide or (3R,5S)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide (Example 58.4), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2), benzhydrazide (Acros).

(3R,5S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3- piperidinesulfonamide or (3S,5R)-N-(4-(2,6-dimethoxyphenyl)- 5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1- methylethoxy)-3-piperidinesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 2 H) 7.36-7.43 (m, 4 H) 7.26-7.34 (m, 2 H) 6.57-6.63 (m, 2 H) 5.11-5.22 (m, 1 H) 4.80-4.90 (m, 1 H) 3.77-3.87 (m, 1 H) 3.76 (s, 3 H) 3.72 (s, 3 H) 3.38 (tt, J = 10.73, 4.51 Hz, 1 H) 3.12 (ddt, J = 12.54, 11.38, 3.74, 3.74 Hz, 1 H) 2.90 (dd, J = 13.01, 11.45 Hz, 1 H) 2.47-2.63 (m, 2 H) 1.65-1.80 (m, 1 H) 1.19 (d, J = 6.01 Hz, 3 H) 1.16 (d, J = 6.12 Hz, 3 H). LCMS-ESI (pos.) m/z: 598.2 (M + H)⁺. 59.0 (3S,5R)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide or (3R,5S)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide (Example 58.5), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2), benzhydrazide (Acros).

(3R,5S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3- piperidinesulfonamide or (3S,5R)-N-(4-(2,6-dimethoxyphenyl)- 5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1- methylethoxy)-3-piperidinesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 2 H) 7.36-7.43 (m, 2 H) 7.26-7.34 (m, 4 H) 6.57-6.63 (m, 2 H) 5.11-5.22 (m, 1 H) 4.80-4.90 (m, 1 H) 3.77-3.87 (m, 1 H) 3.76 (s, 3 H) 3.72 (s, 3 H) 3.38 (tt, J = 10.73, 4.51 Hz, 1 H) 3.12 (ddt, J = 12.54, 11.38, 3.74, 3.74 Hz, 1 H) 2.90 (dd, J = 13.01, 11.45 Hz, 1 H) 2.47-2.63 (m, 2 H) 1.65-1.80 (m, 1 H) 1.19 (d, J = 6.01 Hz, 3 H) 1.16 (d, J = 6.12 Hz, 3 H). LCMS-ESI (pos.) m/z: 598.1 (M + H)⁺. 60.0 5-bromopyridine-3- sulfonamide (CombiBlocks), 2-isothiocyanato-1,3- dimethoxybenzene (Example 1.2), benzhydrazide (Acros).

5-bromo-N-(4-(2,6-dimethoxyphenyl)-5-phenyl-4H-1,2,4-triazol- 3-yl)-3-pyridinesulfonamide. ¹H NMR (400 MHz, DMSO-d₆) δ 13.71 (s, 1 H) 8.91 (dd, J = 8.60, 2.07 Hz, 2 H) 8.33 (t, J = 2.07 Hz, 1 H) 7.41-7.54 (m, 2 H) 7.27-7.40 (m, 4 H) 6.82 (d, J = 8.60 Hz, 2 H) 3.63 (app s, 6 H). LCMS-ESI (pos.) m/z: 516.6 (M + H)⁺. 61.0 (2S,3R)-3-(5- chloropyrimidin-2-yl)butane- 2-sulfonamide (Example 102.4), 4- isothiocyanatooxane (Oakwood Products, Inc.), benzhydrazide (Acros).

(2S,3R)-3-(5-chloro-2-pyrimidinyl)-N-(5-phenyl-4-(tetrahydro- 2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2-butanesulfonamide. ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 2 H) 7.54-7.70 (m, 5 H) 4.18 (tt, J = 12.17, 4.11 Hz, 1 H) 3.94-4.04 (m, 2 H) 3.86-3.93 (m, 1 H) 3.75-3.86 (m, 1 H) 3.24-3.39 (m, 2 H) 2.69 (qd, J = 12.51, 4.77 Hz, 2 H) 1.70 (dtd, J = 10.53, 4.17, 4.17, 2.18 Hz, 2 H) 1.46 (app t, J = 7.00 Hz, 6 H). LCMS-ESI (pos.) m/z: 477.2 (M + H)⁺. 62.0 (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 103.3), 4- isothiocyanatooxane (Oakwood Products, Inc.), benzhydrazide (Acros).

(1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(5-phenyl-4- (tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2- propanesulfonamide. ¹H NMR (400 MHz, CD₃OD) δ 8.86 (s, 2 H) 7.55-7.71 (m, 5 H) 5.12 (d, J = 3.73 Hz, 1 H) 4.23 (tt, J = 12.21, 4.07 Hz, 1 H) 3.99 (br dd, J = 11.61, 4.35 Hz, 2 H) 3.67 (qd, J = 6.98, 3.84 Hz, 1 H) 3.27- 3.41 (m, 7 H) 2.68-2.85 (m, 2 H) 1.74 (br dd, J = 12.54, 1.76 Hz, 2 H) 1.42 (d, J = 7.05 Hz, 3 H). LCMS-ESI (pos.) m/z: 493.1 (M + H)⁺. 63.0 (1S,2S)-1-isopropoxy-1-(5- methylpyrimidin-2- yl)propane-2-sulfonamide (Example 104.0), 4- isothiocyanatooxane (Oakwood Products, Inc.), benzhydrazide (Acros).

(1S,2S)-1-(1-methylethoxy)-1-(5-methyl-2-pyrimidinyl)-N-(5- phenyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-2- propanesulfonamide. ¹H NMR (400 MHz, CDCl₃) δ 12.64 (br s, 1 H) 8.63 (s, 2 H) 7.38- 7.69 (m, 5 H) 4.92 (br d, J = 3.42 Hz, 1 H) 4.28 (br t, J = 11.92 Hz, 1 H) 3.94-4.10 (m, 2 H) 3.83 (br dd, J = 6.53, 4.15 Hz, 1 H) 3.48-3.65 (m, 1 H) 3.35 (br t, J = 11.66 Hz, 2 H) 2.55-2.84 (m, 2 H) 2.35 (s, 3 H) 1.48-1.80 (m, 5 H) 1.10 (br d, J = 5.81 Hz, 3 H) 0.94 (br d, J = 5.91 Hz, 3 H). LCMS-ESI (pos.) m/z: 500.1 (M + H)⁺. 64.0 (3S,5R)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide or (3R,5S)-1-(5- fluoropyrimidin-2-yl)-5- isopropoxypiperidine-3- sulfonamide (Example 58.4), 5-Isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1), Benzhydrazide (Acros).

(3R,5S)-N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-phenyl-4H-1,2,4- triazol-3-yl)-1-(5-fluoro-2-pyrimidinyl)-5-(1-methylethoxy)-3- piperidinesulfonamide or (3S,5R)-N-(4-(4,6-dimethoxy-5- pyrimidinyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-(5-fluoro-2- pyrimidinyl)-5-(1-methylethoxy)-3-piperidinesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.54 (br d, J = 3.37 Hz, 1 H) 8.68 (s, 1 H) 8.47 (s, 2 H) 7.25-7.60 (m, 5 H) 4.92 (br d, J = 11.29 Hz, 1 H) 4.54-4.79 (m, 1 H) 3.91 (app br d, J = 6.23 Hz, 6 H) 3.72 (dq, J = 11.95, 5.79 Hz, 1 H) 3.38-3.50 (m, 1 H) 3.10 (br s, 1 H) 2.72 (br t, J = 12.00 Hz, 1 H) 2.37-2.60 (m, 2 H) 2.32 (br d, J = 11.81 Hz, 1 H) 1.41 (q, J = 11.81 Hz, 1 H) 1.09 (br dd, J = 8.24, 6.16 Hz, 6 H). LCMS-ESI (pos.) m/z: 600.3 (M + H)⁺.

Example 65.0. Preparation of (1R,2S)—N-(5-(4-tert-butylphenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(E)-N′-(2,6-Dimethoxyphenyl)-N-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)carbamimidothioic acid, Example 65.1

To a 20 mL scintillation vial, 1.2 (0.203 g, 0.829 mmol) was suspended in ACN (8 mL) The vial was warmed in a warm water bath to give a clear solution. To the solution at RT, was added 103.0 (0.168 g, 0.859 mmol) followed by portion-wise addition of cesium carbonate (0.367 g, 1.13 mmol). The slightly cloudy mixture was stirred at RT for 15 h to obtain a suspension. LCMS (pos.) m/z: 440.9 (M+H)⁺. The suspension of 65.1 was used as 0.1 M stock solution in the next step.

(1R,2S)—N-(5-(4-tert-Butylphenyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 65.0

To a 20 mL scintillation vial, were added 65.1 (0.1M in ACN, 2.50 mL, 0.250 mmol) and 4-(tert-butyl)benzhydrazide (0.048 g, 0.25 mmol, Frontier Scientific Services, Inc., Newark, Del.) which were then were mixed. The mixture was cooled in an ice-water bath and silver(I) nitrate (0.085 g, 0.50 mmol) was added at once. The cold bath was removed and the brown mixture was stirred at RT. After 15 min, the mixture was filtered through a pad of diatomeceous earth (flushed with ACN). The filtrate was concentrated in GeneVac into a 20 mL scintillation vial. Dioxane (2 mL) was added to the yellow residue followed by methanesulfonic acid (0.073 g, 0.76 mmol). The mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to RT and concentrated. The residue was dissolved in MeOH (˜2 mL) and the mixture was passed through a PS-carbonate column, eluting with MeOH. The filtrate was concentrated and purified by mass-triggered HPLC to afford 65.0, (0.061 g, 0.11 mmol, 42% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 13.08 (br. s., 1H), 8.64 (s, 2H), 7.49 (t, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 4.82 (d, J=3.4 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.41 (dd, J=3.5, 7.0 Hz, 1H), 3.15 (s, 3H), 2.26 (s, 3H), 1.22 (s, 9H), 1.13 (d, J=7.0 Hz, 3H). LCMS (pos.) m/z: 581.1 (M+H)⁺.

A wide variety of sulfonamide tails can be used to synthesize compounds of the invention such as those set forth in PCT/US/2016/033088 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein.

The compounds set forth in the following table were synthesized following the procedure in Example 65.0 using the known starting material as described.

TABLE 15 Example Reagents Structure, Name and and Data 66.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, benzo[d][1,3]dioxole-5- carbohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(1,3-benzodioxol-5-yl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.05 (br. s., 1H), 8.64 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 6.91- 6.87 (m, 1H), 6.86-6.78 (m, 4H), 6.04 (s, 2H), 4.81 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.45-3.37 (m, 1H), 3.18-3.13 (m, 3H), 2.26 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H). LCMS (pos.) m/z: 569.1 (M + H)⁺. 67.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1. 2- fluorobenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(2- fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy- 1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.23 (br. s., 1H), 8.65 (s, 2H), 7.53-7.46 (m, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.29-7.22 (m, 2H), 7.22-7.16 (m, 1H), 6.71 (d, J = 8.5 Hz, 2H), 4.86 (d, J = 3.6 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 3H), 3.44 (dd, J = 3.6, 7.0 Hz, 1H), 3.17 (s, 3H), 2.27 (s, 3H), 1.16 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 543.1 (M + H)⁺. 68.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3,5- bis(trifluoromethyl)benzhydrazide, (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(3,5-bis(trifluoromethyl)phenyl)- 4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)- 1-methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.53 (br. s., 1H), 8.65 (s, 2H), 8.27 (s, 1H), 7.90 (s, 2H), 7.53 (t, J = 8.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.84 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.44 (dd, J = 3.5, 6.9 Hz, 1H), 3.16 (s, 3H), 2.26 (s, 3H), 1.15 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 661.0 (M + H)⁺. 69.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 4- (trifluoromethoxy)benzhydrazide, (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(4- (trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3- yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.23 (br. s., 1H), 8.64 (s, 2H), 7.52-7.43 (m, 3H), 7.41- 7.36 (m, 2H), 6.82 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.70-3.69 (m, 3H), 3.68 (s, 3H), 3.42 (dd, J = 3.6, 7.0 Hz, 1H), 3.15 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 609.1 (M + H)⁺. 70.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3,4- dichlorobenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(3,4-dichlorophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.33 (s, 1H), 8.65 (s, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.29 (dd, J = 1.9, 8.4 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.42 (dd, J = 3.6, 6.9 Hz, 1H), 3.15 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H). LCMS (pos.) m/z: 593.0 (M + H)⁺. 71.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 2,4- dichlorobenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(2,4-dichlorophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.27 (br. s., 1H), 8.65 (s, 2H), 7.73 (d, J = 1.9 Hz, 1H), 7.48- 7.43 (m, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 2H), 4.86 (d, J = 3.4 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.46- 3.41 (m, 1H), 3.18 (s, 3H), 2.27 (s, 3H), 1.16 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 593.0 (M + H)⁺. 72.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3,4- difluorobenzohydrazide (Commerically available from Oakwood Products, Inc., Estill, SC).

(1R,2S)-N-(5-(3,4-difluorophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.27 (br. s., 1H), 8.64 (s, 2H), 7.53-7.44 (m, 2H), 7.38- 7.31 (m, 1H), 7.15 (dd, J = 1.9, 6.5 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.41-3.38 (m, 1H), 3.15 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 561.1 (M + H)⁺. 73.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3- (hydrazinecarbonyl)-N,N- dimethylbenzenesulfonamide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

3-(4-(2,6-dimethoxyphenyl)-5-((((1S,2R)-2- methoxy-1-methyl-2-(5-methyl-2- pyrimidinyl)ethyl)sulfonyl)amino)-4H-1,2,4- triazol-3-yl)-N,N-dimethylbenzenesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.34 (br. s., 1H), 8.65 (s, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.53 (s, 1H), 7.47 (t, J = 8.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.46-3.39 (m, 1H), 3.15 (s, 3H), 2.37 (s, 6H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 632.0 (M + H)⁺. 74.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, tert-butyl (6- (hydrazinecarbonyl)benzo[d]thiazol- 2-yl)carbamate (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(2-amino-1,3-benzothiazol-6-yl)- 4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)- 1-methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.03 (s, 1H), 8.65 (s, 2H), 7.77-7.68 (m, 3H), 7.47 (t, J = 8.5 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 1.7, 8.4 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.42 (dd, J = 3.6, 7.0 Hz, 1H), 3.16 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 597.1 (M + H)⁺. 75.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3-cyano-4- methoxybenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(3-cyano-4-methoxyphenyl)-4- (2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.21 (s, 1H), 8.65 (s, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 2.1, 9.0 Hz, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.16 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). One proton was burned under water peak and was not integrated. LCMS (pos.) m/z: 580.1 (M + H)⁺. 76.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3- methoxybenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(3- methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.14 (br. s., 1H), 8.64 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.29 (d, J = 16.0 Hz, 1H), 7.03-6.95 (m, 2H), 6.85- 6.76 (m, 3H), 4.82 (d, J = 3.5 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.61 (s, 3H), 3.42 (dd, J = 3.6, 7.0 Hz, 1H), 3.16 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 6.9 Hz, 3H). LCMS (pos.) m/z: 555.1 (M + H)⁺. 77.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, benzhydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-phenyl- 4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl- 2-pyrimidinyl)-2-propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.13 (br. s., 1H), 8.65 (s, 2H), 7.49-7.41 (m, 2H), 7.39- 7.28 (m, 4H), 6.80 (d, J = 8.6 Hz, 2H), 4.83 (d, J = 3.5 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.42 (dd, J = 3.6, 6.9 Hz, 1H), 3.16 (s, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 525.1 (M + H)⁺. 78.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 4- methylbenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(4- methylphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.07 (br. s., 1H), 8.65 (s, 2H), 7.46 (t, J = 8.5 Hz, 1H), 7.25- 7.13 (m, 4H), 6.80 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.42 (dd, J = 3.6, 7.0 Hz, 1H), 3.16 (s, 3H), 2.26 (app s, 6H), 1.14 (d, J = 6.9 Hz, 3H). LCMS (pos.) m/z: 539.1 (M + H)⁺. 79.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 2,5- dimethoxybenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(2,5-dimethoxyphenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (300 MHz, CDCl₃) δ 11.16 (s, 1H), 8.60 (s, 2H), 7.26-7.20 (m, 1H), 6.92-6.84 (m, 2H), 6.71 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 8.5 Hz, 2H), 5.01 (d, J = 4.8 Hz, 1H), 3.77 (dd, J = 4.7, 7.0 Hz, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 3.68 (s, 3H), 3.52 (s, 3H), 3.37 (s, 3H), 2.32 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 584.9 (M + H)⁺. 80.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 2,3- dihydrobenzofuran-5- carbohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(2,3-dihydro-1-benzofuran-5-yl)- 4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)- 1-methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (br. s., 1H), 8.65 (s, 2H), 7.47 (t, J = 8.5 Hz, 1H), 7.26 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 3.6 Hz, 1H), 4.52 (t, J = 8.8 Hz, 2H), 3.70 (s, 3H), 3.68 (s, 3H), 3.45-3.37 (m, 1H), 3.16 (s, 3H), 3.11 (t, J = 8.7 Hz, 2H), 2.26 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H). LCMS (pos.) m/z: 567.1 (M + H)⁺. 81.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3- bromobenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(3-bromophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.27 (s, 1H), 8.65 (s, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.54-7.46 (m, 2H), 7.38-7.31 (m, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.46-3.40 (m, 1H), 3.19-3.12 (m, 3H), 2.26 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 603.0/605.0 (M + H/M + 2H)⁺. 82.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 4- phenoxybenzohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(4- phenoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.08 (br. s., 1H), 8.64 (s, 2H), 7.47 (t, J = 8.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.23- 7.17 (m, 1H), 7.05 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.82 (d, J = 3.5 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.42- 3.39 (m, 1H), 3.16 (s, 3H), 2.26 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 617.1 (M + H)⁺. 83.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 4- (diethylamino)benzhydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(5-(4-(diethylamino)phenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (br. s., 1H), 8.64 (s, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 8.5 Hz, 2H), 4.81 (d, J = 3.5 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.40 (dd, J = 3.6, 7.0 Hz, 1H), 3.30 (q, J = 6.9 Hz, 4H), 3.15 (s, 3H), 2.26 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.0 Hz, 6H). LCMS (pos.) m/z: 596.2 (M + H)⁺. 84.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, quinoxaline-6- carbohydrazide (Commerically available from Frontier Scientific Services, Inc., Newark, DE).

(1R,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(6- quinoxalinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy- 1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (500 MHz, DMSO-d₆) δ 13.41 (br. s., 1H), 9.00-8.91 (m, 2H), 8.66 (s, 2H), 8.15 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 1.8, 8.8 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.52 (t, J = 8.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.85 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H), 3.45 (dd, J = 3.5, 6.9 Hz, 1H), 3.17 (s, 3H), 2.27 (s, 3H), 1.16 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 577.1 (M + H)⁺.

Example 85.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(Z)—N′-(2,6-Dimethoxyphenyl)-2-(3-fluorobenzoyl)-N-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximidamide, Example 85.01

3-Fluorobenzohydrazide (0.0413 g, 0.268 mmol, Sigma-Aldrich, St. Louis, Mo.) was added to a scintillation vial containing a suspension of Example 65.1 (˜3 mL, estimated to be 0.1 M). The mixture was chilled in an ice water bath and then silver(I) nitrate (0.0913 g, 0.54 mmol) was added in 2 portions. The cold bath was then removed and the mixture was stirred at RT for 1 h 15 min. The mixture was filtered through a pad of diatomaceous earth (ACN then MeOH as solvent). The filtrate was concentrated, and the product was purified by silica gel column chromatography (25 g, eluent: (3:1 EtOAc/EtOH) in DCM 0%-60%) to afford Example 85.1 (0.104 g, 0.185 mmol, 69.0% yield) as a clear paste. ¹H NMR (300 MHz, CDCl₃) δ 9.36 (br. s., 1H), 8.83-9.09 (m, 1H), 8.53 (s, 2H), 7.58-7.70 (m, 2H), 7.37-7.52 (m, 1H), 7.23 (s, 2H), 6.66 (d, J=8.48 Hz, 2H), 5.03 (d, J=4.24 Hz, 1H), 3.93 (s, 6H), 3.73-3.86 (m, 1H), 3.38 (s, 3H), 2.29 (s, 3H), 1.56 (d, J=7.02 Hz, 3H). One proton was not observed. LCMS (pos.) m/z: 560.9 (M+H)⁺.

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 85.0

In a 20 mL scintillation vial, 85.1 (0.100 g, 0.18 mmol) was mixed into ACN (3 mL). Methanesulfonic acid (0.035 mL, 0.535 mmol) was added, and the vial was capped with a pressure relief cap and stirred at 70° C. overnight. A saturated solution of NaHCO₃ (4 mL) was then added slowly, and the mixture was partitioned between a saturated solution of NaHCO₃ (10 mL) and 10% IPA in CHCl₃ (10 mL). The aqueous phase was extracted with 10% IPA in CHCl₃ (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (10 g, eluent: (3:1 EtOAc/EtOH) in DCM 0%-50%) and then lyophilized to afford Example 85.0 (0.0412 g, 0.076 mmol, 43% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 11.37-10.98 (m, 1H), 8.61 (s, 2H), 7.39 (t, J=8.5 Hz, 1H), 7.26-7.04 (m, 4H), 6.61 (d, J=8.6 Hz, 2H), 4.97 (d, J=4.7 Hz, 1H), 3.79-3.75 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.34 (s, 3H), 2.33 (s, 3H), 1.39 (d, J=7.0 Hz, 3H). LCMS (pos.) m/z: 542.9 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 85.0 using the known starting material as described.

TABLE 16 Example Reagents Structure, Name and and Data 86.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3- cyanobenzohydrazide (Commerically available from Matrix Scientific, Elgin, SC).

(1R,2S)-N-(5-(3-cyanophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (300 MHz, CDCl₃) δ 11.29 (br. s., 1H), 8.60 (s, 2H), 7.72-7.62 (m, 3H), 7.48- 7.37 (m, 2H), 6.62 (d, J = 8.5 Hz, 2H), 4.97 (d, J = 4.5 Hz, 1H), 3.76 (s, 3H), 3.75-3.73 (m, 1H), 3.73 (s, 3H), 3.34 (s, 3H), 2.33 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 550.1 (M + H)⁺. 87.0 (E)-N′-(2,6-dimethoxyphenyl)-N- (((1R,2S)-1-methoxy-1-(5- methylpyrimidin-2-yl)propan-2- yl)sulfonyl)carbamimidothioic acid, Example 65.1, 3- chlorobenzohydrazide (Commerically available from Acros Organics, Fisher Scientific, Pittsburgh, PA).

(1R,2S)-N-(5-(3-chlorophenyl)-4-(2,6- dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2- propanesulfonamide. ¹H NMR (300 MHz, CDCl₃) δ 11.20 (br. s., 1H), 8.60 (s, 2H), 7.45 (d, J = 1.6 Hz, 1H), 7.42- 7.33 (m, 2H), 7.23 (s, 2H), 6.61 (d, J = 8.5 Hz, 2H), 4.97 (d, J = 4.7 Hz, 1H), 3.75 (s, 3H), 3.74- 3.73 (m, 1H), 3.72 (s, 3H), 3.34 (s, 3H), 2.32 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H). LCMS (pos.) m/z: 559.0 (M + H)⁺.

Example 88.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide and (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(S)-Methyl 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate and (R)-methyl 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate, Example 88.1

To a 100-mL round-bottomed flask, were added DME (12 mL), methyl 3-acetylbenzoate (1.00 g, 5.61 mmol, Combi-Blocks, Inc., San Diego, Calif.), and (trifluoromethyl)trimethylsilane (1.10 mL, 6.92 mmol, Sigma-Aldrich, St. Louis, Mo.). The clear solution was placed in an ice-water bath while stirring. Cesium fluoride (0.043 g, 0.281 mmol, Strem Chemicals, Inc., Newburyport, Mass.) was added, and the mixture was stirred at that temperature for 15 min. HCl (5.0 N, 2.3 mL, 11.50 mmol) was added, and the cold bath was removed. The mixture was then stirred at RT overnight. Next, a saturated solution of NaHCO₃ (˜15 mL) was added slowly. The mixture was extracted with EtOAc (2×30 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (25 g, eluent: EtOAc in hexanes, 0%-50%) to afford 88.1 (1.24 g, 5.01 mmol, 89% yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 8.06 (td, J=1.39, 7.75 Hz, 1H), 7.81 (dd, J=0.88, 7.89 Hz, 1H), 7.50 (t, J=7.89 Hz, 1H), 3.95 (s, 3H), 2.50 (s, 1H), 1.83 (d, J=1.02 Hz, 3H). LCMS (pos.) m/z: 249.0 (M+H)⁺.

(S)-3-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzhydrazide and (R)-3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzhydrazide, Example 88.02

In a 250 mL round-bottomed flask, 88.01 (1.24 g, 5.01 mmol) and hydrazine (0.320 mL, 10.20 mmol) were dissolved in MeOH (30 mL). The clear solution was stirred at RT, overnight. Hydrazine (0.5 mL) was added, and the mixture was stirred for 36 h. Hydrazine (0.5 mL) was again added, and the reaction was stirred for 72 h. The reaction mixture was then concentrated. DCM (5 mL) was added to the residue, and the mixture was sonicated to give a white suspension. The resulting solid was collected by filtration, washed with DCM, and air dried to give 88.2 (1.03 g, 4.16 mmol, 83% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.04 (s, 1H), 7.80 (dd, J=1.46, 7.75 Hz, 1H), 7.73 (d, J=7.89 Hz, 1H), 7.42-7.52 (m, 1H), 6.68 (s, 1H), 4.48 (br. s., 2H), 1.71 (s, 3H). LCMS (pos.) m/z: 249.0 (M+H)⁺.

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(3-((1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide and (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 88.0

This compound was prepared following the procedure in Example 1.0 using (1R,2S)-1-(5-methylpyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 103.0), Example 1.2 and 88.2. ¹H NMR (300 MHz, CDCl₃) δ 11.22 (br. s., 1H), 8.59 (s, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.52-7.45 (m, 1H), 7.40-7.31 (m, 2H), 6.58 (dd, J=5.6, 8.6 Hz, 2H), 4.97 (dd, J=1.9, 4.7 Hz, 1H), 3.79-3.65 (m, 7H), 3.34 (s, 3H), 2.61 (d, J=13.2 Hz, 1H), 2.32 (s, 3H), 1.61 (s, 3H), 1.39 (d, J=7.0 Hz, 3H). LCMS (pos.) m/z: 636.9 (M+H)⁺.

Example 89.0. Preparation of (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide

(1R,2S)—N-(4-(2,6-Dimethoxyphenyl)-5-(3-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, Example 89.0

To a stirred mixture of (1R,2S)-1-(5-methylpyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 103.0) (0.0663 g, 0.270 mmol) and Example 1.2 (0.0537 g, 0.28 mmol) in ACN (2 mL) was added cesium carbonate (0.114 g, 0.35 mmol) at RT. The mixture was stirred at RT for 4.5 h. The mixture was cooled in an ice-water bath and 3-(trifluoromethoxy)benzhydrazide (0.0640 g, 0.29 mmol, Matrix Scientific, Elgin, S.C.) was added followed by silver(I) nitrate (0.102 g, 0.60 mmol, Sigma-Aldrich, St. Louis, Mo.). The ice bath was removed and the mixture was stirred at RT for 20 min. The reaction mixture was filtered through a pad of diatomaceous earth (eluent:ACN then MeOH) and concentrated in vacuo to give a dark residue. 1,4-Dioxane (2 mL) was added to the residue followed by methanesulfonic acid (0.053 mL, 0.811 mmol, Sigma-Aldrich, St. Louis, Mo.). The dark mixture was stirred at 80° C. under N₂ overnight. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate (10 mL) and 10% IPA in CHCl₃ (10 mL). The aqueous phase was extracted with 10% IPA in CHCl₃ (10 mL). The combined organic phases were dried by passing through a Chem Elute extraction cartridge (eluting with 10% IPA in chloroform, 3×10 mL). The organic phase was concentrated and the product was purified by silica gel column chromatography (25 g, eluent: (3:1 EtOAc/EtOH) in DCM 0%-50%) and lyophilized to give 89.0 (0.109 g, 0.179 mmol, 66.2% yield) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 11.19 (br. s., 1H), 8.60 (s, 2H), 7.45-7.31 (m, 3H), 7.24 (s, 2H), 6.60 (d, J=8.6 Hz, 2H), 4.97 (d, J=4.5 Hz, 1H), 3.81-3.74 (m, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.35 (s, 3H), 2.33 (s, 3H), 1.39 (d, J=7.0 Hz, 3H). LCMS (pos.) m/z: 608.9 (M+H)⁺.

Example 91.1. Preparation of 2-methyl-2H-indazole-7-carbohydrazide

2-Methyl-2H-indazole-7-carbohydrazide, Example 91.1

To a solution of 7-methoxycarbonyl-2-methylindazole (1 g, 5.26 mmol) in MeOH (7.97 mL) was added hydrazine, monohydrate (0.786 mL, 10.52 mmol). The mixture was then heated to 80° C. After 12 hrs, the reaction showed complete conversion to product by LCMS. The reaction was cooled to RT and EtOAc was added. The resulting mixture was stirred for 30 min. The mixture was concentrated in vacuo to yield 2-methyl-2H-indazole-7-carbohydrazide (1.05 g, 5.52 mmol). This material was carried forward without further purification. ¹H NMR (500 MHz, DMSO-d₆) δ 1.74 (s, 1H) 4.26 (s, 3H) 4.72 (br s, 2H) 7.20 (t, J=7.66 Hz, 1H) 7.94 (d, J=8.30 Hz, 1H) 7.99 (d, J=7.01 Hz, 1H) 8.58 (s, 1H).

The compounds set forth in the following table were synthesized following the procedure in Example 91.1 using the known starting material as described.

TABLE 17 Ex- ample Reagents Structure, Name and Data 95.1 Methyl isoquinoline-5- carboxylate (commercially available from Combi- Blocks, Inc.).

Isoquinoline-5-carbohydrazide. LCMS-ESI (pos.) m/z: 188.2 (M + H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 85.0 using the known starting material as described.

TABLE 18 Example Reagents Structure, Name and Data 90.0 Quinoline-5-carbohydrazide (commercially available from Frontier Scientific Services Inc). Isothiocyanato-1,3- dimethoxybenzene (Example 1.2). (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2- yl)propane-2-sulfonamide (Example 103.3).

¹H NMR (500 MHz, CDCl₃) δ 11.13-11.28 (m, 1 H) 8.91-9.02 (m, 1 H) 8.52-8.58 (m, 2 H) 8.42-8.49 (m, 1 H) 8.11-8.18 (m, 1 H) 7.54- 7.61 (m, 1 H) 7.45-7.52 (m, 1 H) 7.38-7.43 (m, 1 H) 7.19-7.26 (m, 1 H) 6.40-6.49 (m, 2 H) 5.07-5.12 (m, 1 H) 3.56-3.65 (m, 7 H) 3.36- 3.42 (m, 3 H) 2.57-2.62 (m, 3 H) 1.32-1.36 (m, 3 H). LCMS-ESI (pos.) m/z: 576.2 (M + H)⁺. 91.0 2-methyl-2H-indazole- 7-carbohydrazide (Example 91.1). isothiocyanato-1,3- dimethoxybenzene (Example 1.2). (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 103.3).

¹H NMR (400 MHz, DMSO-d₆) δ 13.00-13.17 (m, 1 H) 8.84-9.00 (m, 2 H) 8.29-8.44 (m, 1 H) 7.68-7.86 (m, 1 H) 7.25-7.42 (m, 1 H) 7.00-7.13 (m, 1 H) 6.88-6.98 (m, 1 H) 6.55-6.72 (m, 2 H) 4.77-4.89 (m, 1 H) 4.03-4.21 (m, 3 H) 3.55-3.65 (m, 6 H) 3.47-3.53 (m, 1 H) 3.20-3.24 (m, 3 H) 1.12-1.25 (m, 3 H). LCMS-ESI (pos.) m/z: 599.2 (M + H)⁺. 92.0 2-methyl-2H-indazole- 7-carbohydrazide (Example 99.1). isothiocyanato-1,3- dimethoxybenzene (Example 1.2). (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2- yl)propane-2-sulfonamide (Example 102.3).

¹H NMR (500 MHz, DMSO-d₆) δ 13.06-13.29 (m, 1 H) 8.50-8.58 (m, 1 H) 8.42-8.47 (m, 1 H) 8.34-8.39 (m, 1 H) 7.72-7.79 (m, 1 H) 7.27-7.35 (m, 1 H) 7.02-7.08 (m, 1 H) 6.90-6.97 (m, 1 H) 6.63-6.70 (m, 2 H) 4.86-4.92 (m, 1 H) 4.08-4.16 (m, 3 H) 3.55-3.63 (m, 6 H) 3.45-3.50 (m, 1 H) 3.35-3.36 (m, 3 H) 3.23 (s, 3 H) 1.07-1.13 (m, 3 H). LCMS-ESI (pos.) m/z: 579.2 (M + H)⁺. 93.0 2-methyl-2H-indazole- 7-carbohydrazide (Example 99.1). 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1). (1R,2S)-1-(5- methylpyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide (Example 103.0).

¹H NMR (500 MHz, DMSO-d₆) δ 13.31-13.49 (m, 1 H) 8.52-8.55 (m, 1 H) 8.47-8.49 (m, 1 H) 8.43-8.45 (m, 1 H) 8.35-8.37 (m, 1 H) 7.83-7.87 (m, 1 H) 7.38-7.43 (m, 1 H) 7.07-7.13 (m, 1 H) 4.90-4.94 (m, 1 H) 4.01-4.04 (m, 3 H) 3.76-3.79 (m, 6 H) 3.50-3.52 (m, 1 H) 3.47-3.49 (m, 3 H) 3.22-3.25 (m, 3 H) 1.11-1.15 (m, 3 H). LCMS- ESI (pos.) m/z: 581.2 (M + H)⁺. 94.0 2-methyl-2H-indazole- 7-carbohydrazide (Example 99.1). 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1). (1R,2S)-1-(5- chloropyrimidin-2- yl)-1-methoxypropane- 2-sulfonamide (Example 103.3).

¹H NMR (500 MHz, DMSO-d₆) δ 8.92-8.99 (m, 2 H) 8.40-8.45 (m, 1 H) 8.32-8.38 (m, 1 H) 7.80-7.84 (m, 1 H) 7.82 (br d, J = 8.2 Hz, 1 H) 7.37-7.41 (m, 1 H) 7.07-7.11 (m, 1 H) 4.85-4.88 (m, 1 H) 4.01- 4.03 (m, 3 H) 3.75-3.79 (m, 7 H) 3.21-3.23 (m, 3 H) 1.22-1.25 (m, 3 H). LCMS-ESI (pos.) m/z: 601.2 (M + H)⁺. 95.0 Isoquinoline-5- carbohydrazide (Example 95.1). isothiocyanato-1,3- dimethoxybenzene (Example 1.2). (1R,2S)-1-methoxy-1-(5- methylpyrimidin-2- yl)propane-2- sulfonamide (Example 103.0).

¹H NMR (500 MHz, DMSO-d₆) δ 13.42-13.55 (m, 1 H) 9.42-9.49 (m, 1 H) 8.60-8.63 (m, 1 H) 8.53-8.55 (m, 1 H) 8.45-8.47 (m, 1 H) 8.28-8.31 (m, 1 H) 7.88-7.91 (m, 1 H) 7.66-7.73 (m, 2 H) 7.25-7.31 (m, 1 H) 6.59-6.64 (m, 2 H) 4.89-4.92 (m, 1 H) 3.57-3.60 (m, 7 H) 3.36-3.40 (m, 3 H) 3.23-3.26 (m, 3 H) 1.10-1.15 (m, 3 H). LCMS- ESI (pos.) m/z: 576.2 (M + H)⁺.

Example 96.0. Preparation of (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide

2-Isothiocyanato-1,3-dimethoxypropane, Example 96.1

To a dry 200 mL round-bottomed flask was added di(2-pyridyl) thionocarbonate (5.34 g, 23.00 mmol) in DCM (73.0 mL). 2-Amino-1,3-dimethoxypropane (commercially available from Combi-Blocks Inc., 2.61 g, 21.90 mmol) in DCM (15 mL) was then added dropwise via a addition funnel over 5 min at RT. The reaction mixture was stirred at RT for 3.5 h. The reaction mixture was concentrated in vacuo. The material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in heptanes, to provide Example 96.1 (3.28 g, 20.34 mmol, 93% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.95 (quin, J=5.49 Hz, 1H) 3.50-3.60 (m, 4H) 3.41 (s, 6H). Mass Spectrum (pos.) m/z: 162.2 (M+H)⁺.

(1R,2S)-1-(5-Chloro-2-pyrimidinyl)-N-(4-(1,3-dimethoxy-2-propanyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide, Example 96.0

Example 96.0 was prepared from Example 96.1, benzhydrazide (commercially available from Acros Organics), and (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide, Example 103.3 following the procedures described in Example 21.0. ¹H NMR (500 MHz, DMSO-d₆) δ 13.04 (br s, 1H) 8.96 (s, 2H) 7.47-7.78 (m, 5H) 4.98 (br d, J=3.63 Hz, 1H) 4.39 (dt, J=8.95, 4.61 Hz, 1H) 4.32 (br s, 1H) 3.99-4.20 (m, 2H) 3.45-3.61 (m, 3H) 3.20 (s, 3H) 3.19 (s, 3H) 3.17 (s, 3H) 1.30 (br d, J=7.01 Hz, 3H). Mass Spectrum (pos.) m/z: 511.2 (M+H)⁺

Example 97.0. Preparation of (1R,2S)-1-(5-chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclopropyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide

1-Isothiocyanato-1-(methoxymethyl)cyclopropane, Example 97.1

To a dry 200 mL round-bottomed flask was added 1-(methoxymethyl)cyclopropanamine hydrochloride (commercially available from J&W Pharm Lab, 2.06 g, 14.97 mmol) and di(2-pyridyl) thionocarbonate (3.65 g, 15.72 mmol) in DCM (49.9 mL). Hunig's base (2.86 mL, 16.47 mmol) in DCM (15 mL) was added dropwise via an addition funnel over 5 min at RT with stirring. The reaction mixture was stirred at RT for 3.5 h. The reaction mixture was concentrated in vacuo. The material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide Example 97.1(1.88 g, 13.13 mmol, 88% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.47 (s, 2H), 3.43 (s, 3H), 1.06-1.16 (m, 2H), 0.81-0.94 (m, 2H).

(1R,2S)-1-(5-Chloro-2-pyrimidinyl)-1-methoxy-N-(4-(1-(methoxymethyl)cyclopropyl)-5-phenyl-4H-1,2,4-triazol-3-yl)-2-propanesulfonamide, Example 97.0

Example 97.0 was prepared from Example 97.1, benzhydrazide (commercially available from Acros Organics) and (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide, Example 103.3, following the procedure as described in Example 21.0. ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (br s, 1H) 8.95 (s, 2H) 7.95 (br d, J=7.01 Hz, 2H) 7.44-7.62 (m, 3H) 5.01 (br d, J=3.63 Hz, 1H) 3.99-4.14 (m, 1H) 3.48 (br dd, J=6.75, 3.37 Hz, 1H) 3.31-3.33 (m, 3H) 3.17 (s, 3H) 3.13 (br s, 3H) 1.31 (br d, J=7.01 Hz, 3H) 0.97 (br s, 2H). Mass Spectrum (pos.) m/z: 493.2 (M+H)⁺.

The compounds in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 19 Example Reagents Structure, Name and Data 98.0 (1R,2S)-1-(5- chloropyrimidin-2-yl)- 1-methoxypropane- 2-sulfonamide Example 103.3. benzhydrazide (commercially available from Acros Organics). 1-isothiocyanato-1- methylcyclopropane (commercially available from Enamine).

¹H NMR (500 MHz, DMSO-d₆) δ 12.94 (s, 1H), 8.95 (s, 2H), 7.72- 7.65 (m, 2H), 7.62-7.54 (m, 3H), 4.99 (d, J = 3.9 Hz, 1H), 3.57-3.44 (m, 1H), 3.12 (s, 3H), 1.62 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H), 0.86- 0.65 (m, 4H). Mass Spectrum (pos.) m/e: 463.0 (M + H)⁺. 99.0 (1S,2S)-1-isopropoxy-1- (5-methylpyrimidin-2- yl)propane-2- sulfonamide Example 104.0. benzhydrazide (commercially available from Acros Organics). 1-isothiocyanato-1- methylcyclopropane (commercially available from Enamine).

¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (br s, 1H), 8.68 (s, 2H), 7.71-7.65 (m, 2H), 7.62-7.54 (m, 3H), 4.85 (d, J = 7.8 Hz, 1H), 3.59 (quin, J = 7.3 Hz, 1H), 3.27 (td, J = 6.1, 12.2 Hz, 1H), 2.27 (s, 3H), 1.64 (s, 3H), 1.04 (d, J = 7.3 Hz, 3H), 0.99 (d, J = 6.0 Hz, 3H), 0.98- 0.78 (m, 3H), 0.72-0.57 (m, 4H). Mass Spectrum (pos.) m/e: 471.2 (M + H)⁺. 110.0 Benzhydrazide (commericially available from Sigma-Aldrich, Inc.). 2-isothiocyanatopropane (Comercially available from Sigma-Aldrich Inc.). (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 103.3).

¹H NMR (600 MHz, DMSO-d₆) δ 12.97-13.07 (m, 1 H) 8.93-9.01 (m, 2 H) 7.54-7.66 (m, 5 H) 4.92-4.98 (m, 1 H) 4.20-4.28 (m, 1 H) 3.50-3.57 (m, 1 H) 3.13-3.19 (m, 3 H) 1.40-1.46 (m, 6 H) 1.27-1.34 (m, 3H) M/Z: 451.2 (M + H)⁺.

Example 100.0. Preparation of N,N-bis(4-methoxybenzyl)ethanesulfonamide

Bis(4-methoxybenzyl)amine, Example 100.1

4-Methoxybenzylamine (600 g, 4.37 mol) and 4-methoxybenzaldehyde (532 mL, 4.37 mol) were added to a 10 L round bottomed flask at ambient temperature. An exotherm was observed and a white precipitate formed. The mixture was stirred for 1 h and then anhydrous EtOH (4.8 L) was added. After an additional 15-30 min at RT, sodium borohydride granules (99 g, 2.62 mol) were added portionwise over ˜2 h (Note: During the addition of NaBH₄, the internal temperature of the reaction rose to 42° C.), and the reaction was further stirred at RT overnight. The reaction was then slowly quenched with water (600 mL) and then concentrated in vacuo. The residue was partitioned between water (4 L) and DCM (4 L), and the aqueous layer was extracted with more DCM (2×2 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide 100.1 (1.112 kg, 99% yield) as a semi-solid. The material was used directly in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃) δ 7.28 (t, J=7.1 Hz, 4H), 6.89 (d, J=8.6 Hz, 4H), 3.83 (m, 6H), 3.76 (s, 4H). LCMS-ESI (pos.) m/z: 258.4 (M+H)⁺.

N,N-Bis(4-methoxybenzyl)ethanesulfonamide, Example 100.0

To an ice-cooled solution of 100.1 (900 g, 3.49 mol) in DCM (9 L) was added TEA (634 mL, 4.55 mol) followed by ethanesulfonyl chloride (399 mL, 4.19 mol, 1.2 eq) dropwise (Note: The internal temperature was kept between 5-10° C. during the addition of the ethane sulfonyl chloride). Once the addition was complete, the cooling bath was removed. After 1.5 h, TLC showed complete loss of starting material. The reaction was quenched with water (4 L) and the layers were separated. The aqueous layer was then extracted with more DCM (2×2 L). The combined organic layers were washed with brine (2×1 L), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed onto a plug of silica gel purified by silica gel chromatography (eluent: 10-80% EtOAc in hexanes) to provide 100.0 (1.125 kg, 92% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 7.23 (dd, J=2.1, 6.6 Hz, 4H), 6.90 (dd, J=2.1, 6.6 Hz, 4H), 4.29 (s, 4H), 3.83 (s, 6H), 2.92 (q, J=7.4 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H). LCMS-ESI (pos.) m/z: 372.2 (M+Na)⁺.

Example 101.0. Preparation of N,N-bis(4-methoxybenzyl)methanesulfonamide

N,N-Bis(4-methoxybenzyl)methanesulfonamide, Example 101.0

To a stirred solution of 100.1 (100 g, 0.39 mol) in DCM (1 L) was added TEA (71 mL, 0.51 mol), followed by dropwise addition of methanesulfonyl chloride (36 mL, 0.47 mol). The internal temperature was kept between 5-10° C. during the addition of methane sulfonyl chloride. Once the addition was complete, the cooling bath was removed and the mixture was stirred at RT until TLC analysis indicated that the reaction was complete. Thereafter, water (1 L) was added, the layers were separated and the aqueous layer was extracted with DCM (2×500 mL). The combined organic layers were washed with brine (2×1 L), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified on a silica gel column, employing a gradient of 10-80% EtOAc in hexanes, to afford 120 g (0.36 mol, 92%) of 101.0 as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 7.26 (dd, J=2.12, 6.60 Hz, 4H) 6.91 (dd, J=2.12, 6.62 Hz, 4H) 4.28 (s, 4H) 3.83 (s, 6H) 2.75 (s, 3H).

Example 102.0. Preparation of (2S,3R)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

(E)-2-(But-2-en-2-yl)-5-methylpyrimidine, Example 102.01

2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2-yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd₂(dba)₃ (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100° C. for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 102.01 (19 g, 125 mmol, 83% yield).

2-(2-Chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine, Example 102.02

To a solution of pyrimidine-2-thiol (14.8 g, 132 mmol) in DCM (440 mL) was added sulfuryl chloride (10.73 mL, 132 mmol). The reaction was stirred at 0° C. for 1 h and a further 1 h at 23° C. To the cloudy reaction mixture was added (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 102.01 (20 g, 132 mmol) dropwise, and the mixture was further stirred for 2 h. The reaction mixture was then concentrated in vacuo. Aqueous sodium bicarbonate was added to the mixture to neutralize the reaction mixture. The reaction was then extracted with EtOAc and concentrated in vacuo. The residue was purified on silica gel with 0-25% EtOAc in hexanes to give the desired product 2-(2-chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine 102.02 (30 g, 76% yield).

2-(2-Chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine, Example 102.03

To a solution of 2-(2-chloro-3-(pyrimidin-2-ylthio)butan-2-yl)-5-methylpyrimidine 102.02 (30 g, 100 mmol) in DCM (201 mL) was added meta-chloroperoxybenzoic acid (45.0 g, 201 mmol). The reaction was stirred at 23° C. for 1 d. The reaction was concentrated in vacuo and aqueous sodium bicarbonate and sodium thiosulfate were added. The mixture was extracted with EtOAc and concentrated in vacuo to give the desired product 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine 102.03 (33.2 g, 100 mmol, 100% yield).

Potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate, Example 102.04

To a solution of 2-(2-chloro-3-(pyrimidin-2-ylsulfonyl)butan-2-yl)-5-methylpyrimidine 102.03 (33 g, 100 mmol) in MeOH (249 mL) was added potassium carbonate (27.6 g, 200 mmol). The reaction was stirred at 23° C. for 16 h. The reaction was concentrated in vacuo to give the desired product potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate 102.04 (21.57 g, 100% yield) which was used without further purification.

(E)-3-(5-Methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 102.05

To a solution of potassium (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfinate (Example 102.04, 21.57 g, 85 mmol) in water (424 mL, 85 mmol) was added potassium acetate (5.30 mL, 85 mmol), followed by amidoperoxymonosulfuric acid (19.18 g, 170 mmol). The reaction was then stirred at 23° C. for 24 h. The reaction was extracted with EtOAc and concentrated in vacuo. The product thus obtained was purified on silica gel eluting with 0-50% EtOAc in hexanes to give the desired product (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfonamide 102.05 (12 g, 61.2% yield).

(2S,3R)-3-(5-Methylpyrimidin-2-yl)butane-2-sulfonamide, Example 102.0

A 900 mL pressure reactor was charged under nitrogen flow with (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfonamide, Example 102.05 (40.00 g, 0.1760 mol, 1 equiv), zinc trifluoromethane sulfonate (12.79 g, 0.0352 mol, 0.2 equiv, Aldrich), bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1.43 g, 0.00352 mol, 0.02 equiv, Stream Chemicals, Inc.), (S)-1-[(R)-2-(di-1-naphthylphosphino)ferrocenyl]-ethyl-di-tert.-butylphosphine (2.60 g, 0.00405 mol, 0.023 equiv, Solvias) and MeOH (520 mL). The mixture was purged with nitrogen and then with hydrogen and the mixture was stirred under 3-4 bars of hydrogen for 20 h. The reaction was monitored by HPLC and showed a complete conversion. The reactor was then purged with nitrogen and the resulting suspension was concentrated at 35° C. under industrial vacuum to give an initial product as an orange solid. The initial product was mixed with EtOH (742 mL) and the resulting suspension was stirred at 20-25° C. for 40 min. The solid was filtered, washed with EtOH (2×97 mL) and dried at 40° C. under vacuum to give the title compound as a white powder (85.2% yield, 99% ee). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (s, 2H), 6.84 (s, 2H), 3.69 (tt, J=12.4, 4.5 Hz, 2H), 2.25 (s, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.20 (d, J=7.0 Hz, 3H). LCMS (ESI, positive ion) m/z; 230.1 (M+H)⁺.

The compounds in the following table were synthesized following the procedure in Example 102.0 using the known starting material as described.

TABLE 20 Example Reagents Structure, Name and Data 102.1 2-chloro-5-fluoro-pyrimidine.

LCMS ESI (pos.) m/z: 234.2 (M + H)⁺. 102.2 2-bromo-5-methylpyrazine. The title compound was the first isomer to elute under the following SFC conditions: Run on Thar 200 SFC with 250 × 30 mm AD-H column with 20 mL/min MeOH (+ 20 mM NH₃) + 80 g/min CO₂, 20% co-solvent at 100 g/min. Temperature. = 29° C., Outlet pressure = 100 bar, Wavelength = 271 nm. Injected 1.0 mL of 550 mg of the enantiomerically

enriched product dissolved in ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J = 6.5 Hz, 2H), 20 mL MeOH:DCM, 15:5; 6.84 (s, 2H), 3.63 (qd, J = 7.0, 4.3 Hz, 1H), 3.44 (qd, J = c = 27.5 mg/mL and 27.5 mg 7.0, 4.3 Hz, 1H), 2.47 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.23 per injection. Cycle time 5.0 (d, J = 7.0 Hz, 3H). LCMS (ESI, pos.) m/z; 230.0 (M + H)⁺. min, run time 13 min. 102.3 2-bromo-5-methylpyrazine. The title compound is the enantiomer of Example 102.2. Example 102.3 is the second isomer to elute from AD-H column on subjecting the enantiomerically enriched product to the SFC conditions described in Example 102.2.

LCMS ESI (pos.) m/z: 230.0 (M + H)⁺. 102.4 2-chloro-5-chloro-pyrimidine. Recrystallization: Example 102.4 (38 g, 90% ee) was dissolved in IPA (400 mL) at 70° C.

¹H NMR (400 MHz, DMSO-d₆) δ 8.93-8.85 (m, 2H), 6.86 (d, J = 4.0 Hz, 2H), 3.73-3.59 (m, 2H), 1.31 (dt, J = 7.3, 2.4 Hz, 3H), 1.25-1.19 (m, 3H). LCMS (ESI pos.) m/z: 250.2 (M + H)⁺. 102.5 2-bromo-5-methoxypyrazine.

¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 1.4 Hz, 1H), 6.84 (s, 2H), 3.90 (d, J = 1.5 Hz, 3H), 3.62 (dd, J = 7.1, 4.3 Hz, 1H), 3.42-3.38 (m, 1H), 1.32 (d, J = 1.5 Hz, 3H), 1.23-1.21 (m, 3H). LCMS (ESI pos.) m/z: 246.2 (M + H)⁺.

Example 103.0. Preparation of (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine, Example 103.01

To a 500 mL round bottomed flask was added 2-chloro-5-methylpyrimidine (12 g, 93 mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N₂ (5×) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added. A reflux condenser was attached, and the reaction was warmed to 90° C. in an oil bath and stirred under N₂ for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2×250 mL). The organic layers were combined, dried (MgSO₄), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine 103.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J=15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J=6.8, 1.6 Hz, 3H). LCMS (ESI pos.) m/z: 135.2 (M+H)⁺.

(1R,2R)-1-(5-Methylpyrimidin-2-yl)propane-1,2-diol, Example 103.02

Racemic conditions. To a solution of (E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine, 103.01 (5.75 g, 42.9 mmol) and 4-methylmorpholine-4-oxide (7.53 g, 64.3 mmol) in acetone (60 mL) and water (6 mL) was added osmium tetroxide, 4 wt. %, in water (0.681 mL, 0.111 mmol). The resulting reaction mixture was stirred at RT under N₂ for 21.5 h. LCMS showed complete conversion to a product corresponding to the mass of the desired product (M+H)⁺=169). The reaction was passed through a Varian Chem-Elut cartridge to remove water and was then concentrated in vacuo. Water was still present, and the residue was dissolved in DCM, dried (MgSO₄), and concentrated. The residue was purified by flash chromatography (120 g SiO₂, 0-10% MeOH/DCM) to give the racemic syn-diol (1S,2S)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol and (2R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (5.85 g, 34.8 mmol, 81% yield) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.59 (s, 2H), 4.67 (br. s., 1H), 4.33 (br. s., 1H), 4.09-4.25 (m, 1H), 2.86 (d, J=7.2 Hz, 1H), 2.36 (s, 3H), 1.30 (d, J=6.6 Hz, 3H). LCMS (ESI pos.) m/z: 169.2 (M+H).

Chiral conditions. A batch of AD-mix-beta was prepared from: K₂OsO₂(OH)₄ (26 mg, 0.07 mmol); K₃Fe(CN)₆ (16.4 g, 49.9 mmol); K₂CO₃ (6.89 g, 49.9 mmol); and 1,4-bis[(S)-[(2R 4S,5R)-5-ethylquinuclidin-2-yl]-(6-methoxy-4-quinolyl)methoxy]phthalazine (DHQD)₂PHAL, 125 mg, 0.16 mmol). In a 50 mL round bottom flask was added t-BuOH (5 mL), water (5.00 mL), and 1.4 g of AD-mix-beta (prepared above) and methanesulfonamide (95 mg, 1.00 mmol). The mixture was stirred at RT until clear, and then cooled to 0° C. (E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine (Example 103.01 168 mg, 1 mmol) in t-BuOH (1 mL) was added, and the slurry was stirred at 0° C. for 2 h. LCMS (1.5 h) showed ˜10% conversion. The reaction was allowed to warm slowly to RT as the ice bath melted, and it was stirred an additional 22 h. LCMS showed ˜90% conversion. The reaction was then quenched with saturated aqueous sodium sulfite (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were washed with 2 N NaOH (10 mL), dried (MgSO₄), and concentrated. The aqueous layer was extracted with DCM (2×50 mL), EtOAc (2×50 mL), and 10% IPA in CHCl₃ (2×50 mL). The combined organic layers were concentrated and the residue purified by flash column chromatography (12 g SiO₂, 5-100% 3:1 EtOAc:EtOH/heptane) to give (1R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (Example 103.02, 88.6 mg, 0.527 mmol, 52.7% yield) as a clear, colorless oil. Chiral Analysis: SFC Chiral Analysis shows the % ee to be 94.8% using an AS-H (100×2.1 mm, 3 μm), 10% organic modifier (IPA with 20 mM ammonia), 90% carbon dioxide. F=1.0 mL/min, column temperature=RT, BRP=105 bar.

5-Methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine, Example 103.03

To a solution of syn-diol (1R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol 103.02 (1.46 g, 8.68 mmol) in DCM (25 mL) (cooled with a RT water bath) was added 1,1,1-trimethoxyethane (2.50 mL, 2.29 mmol). Chlorotrimethylsilane (2.50 mL, 19.7 mmol) was then added in 2 portions 5 min apart. The reaction had a small exotherm on the first portion of addition of TMSCl (23-28° C.). The reaction was stirred at RT under N₂ 23 h. LCMS indicated incomplete conversion. Thus, an additional 1.25 equiv. of 1,1,1-trimethoxyethane (1.25 mL, 9.95 mmol) and chlorotrimethylsilane (1.25 mL, 9.85 mmol) were added, and the reaction was stirred for an additional 24 h. LCMS; ((M+H)⁺=229). The reaction was then concentrated in vacuo. The residue was dissolved in MeOH (20 mL), potassium carbonate (1.50 g, 10.85 mmol) was added, and the reaction was stirred at RT for 4 h. LCMS (4 h) showed complete conversion to product corresponding to the desired epoxide LCMS; ((M+H)⁺=151). The reaction was then filtered, the filter cake washed with DCM (5 mL), and the combined filtrates concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 0-100% EtOAc/hexanes) to afford 5-methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine 103.03 (1.00 g, 6.6 mmol, 77%) as a clear, light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.54 (s, 2H), 3.81 (d, J=1.9 Hz, 1H), 3.32-3.53 (m, 1H), 2.31 (s, 3H), 1.50 (d, J=5.1 Hz, 3H). LCMS (ESI pos.) m/z: 151.2 (M+H)⁺.

(1R,2S)-2-(Benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol, Example 103.04

To a solution of 5-methyl-2-((2R,3R)-3-methyloxiran-2-yl)pyrimidine 103.03 (250 mg, 1.33 mmol) in DCM (5 mL) was added benzo[d]thiazole-2-thiol (245 mg, 1.465 mmol), followed by tris(((trifluoromethyl)sulfonyl)oxy)ytterbium (83 mg, 0.133 mmol). The suspension was heated in a 35° C. heating block for 17 h and showed 100% conversion to the desired product. The reaction was cooled to RT, loaded on a plug of silica, and purified by flash chromatography (12 g SiO₂, 5-100% 3:1 EtOAc:EtOH/heptane) to afford (1R,2S)-2-(benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol 103.04 (428 mg, 1.35 mmol, 100% yield) as a clear colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 8.60 (s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.71-7.81 (m, 1H), 7.42 (td, J=7.7, 1.3 Hz, 1H), 7.27-7.35 (m, 1H), 5.31 (s, 1H), 4.70 (qd, J=7.1, 3.1 Hz, 1H), 2.32 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). LCMS (ESI pos.) m/z: 318.2 (M+H)⁺.

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole, Example 103.05

To a 50 mL flask equipped with a magnetic stirrer was charged a (1R,2S)-2-(benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol 103.04 (350 mg, 1.103 mmol) in 2-methyltetrahydrofuran (1.1 mL). The reaction mixture was cooled to −78° C. and potassium bis(trimethylsilyl)amide (1M solution in THF, 1.32 μL, 1.32 mmol)) was added dropwise (total addition time: 2 min., turned to yellow solution). The resulting mixture was stirred for 1 h and then methyl trifluoromethanesulfonate (374 μL, 3.31 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. LCMS showed complete conversion to the product. The reaction mixture was quenched by saturated aqueous NH₄Cl solution (30 mL) at −78° C. The reaction was allowed to warm to RT, and the aqueous layer was back extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The material thus obtained was purified by chromatography through a Biotage 50 g ultra silica gel column, eluting with a gradient of 0-25% EtOAc in hexanes, to provide 2-(((1R,2S))-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole 103.05 (0.32 g, 75% for two runs) as a light-yellow oil.

2-(((1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole, Example, Example 103.06

A solution of 2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole 103.05 (313 mg, 0.94 mmol) in DCM (2.8 mL) at 0° C. was treated with 3-chloroperoxybenzoic acid, 77% max. (476 mg, 2.13 mmol). The reaction was stirred at 0° C. for 1 h before the ice bath was removed. LCMS showed desired product, sulfoxide and the presumed sulfoxide/sulfone. The mixture was allowed to warm to ambient temperature and stirred for an additional 40 h. The reaction was quenched with saturated aqueous sodium bisulfite (6 mL), saturated aqueous sodium bicarbonate (5 mL), and was then stirred for 10 min. The reaction was extracted with EtOAc (2×20 mL) and the organic layers were combined, washed with saturated aqueous NaHCO₃ (10 mL), brine (10 mL), dried (MgSO₄) and filtered. Iodide/starch strip indicator showed no peroxide was present. The filtrates were concentrated to give a clear, colorless oil (360 mg). Purification of the residue by flash chromatography (40 g SiO₂, 0-100% 3:1 EtOAc:EtOH/heptane) gave 2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole 11.6 (285 mg, 0.78 mmol, 83% yield, 77% purity) as a white foam. ¹H NMR (300 MHz, CDCl₃) δ 8.57 (s, 2H), 8.18-8.28 (m, 1H) 7.97-8.05 (m, 1H), 7.54-7.67 (m, 2H), 5.25-5.34 (m, 1H), 4.23 (qd, J=7.2, 3.1 Hz, 1H), 3.41 (s, 3H), 2.31 (s, 3H), 1.49 (d, J=7.2 Hz, 3H). LCMS (ESI pos.) m/z: 364.0 (M+H).

Potassium (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfinate, Example 103.07.

To a solution of 2-(((1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole 103.06 (268 mg, 0.74 mmol) in MeOH (1843 μL) was added potassium carbonate (204 mg, 1.48 mmol). The reaction was stirred at RT for 17 h. LCMS showed desired product formation as the sulfinic acid 11.7. LCMS ((M+H)+=231.1). The reaction was concentrated in vacuo (yellow solid) and used directly in the following step. Note: Epimerization occurred in this reaction (˜15%).

(1R,2S)-1-Methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 103.0

To a suspension of potassium (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfinate (Example 103.07, 198 mg, 0.74 mmol) in water (3.7 mL) was added potassium acetate (72.4 mg, 0.74 mmol), followed by hydroxylamine-o-sulfonic acid, 97% (167 mg, 1.476 mmol). The reaction mixture was stirred at RT for 4.5 h. LCMS showed desired product formation plus a small peak that corresponded to the stereoisomer. The reaction mixture was extracted with EtOAc (2×) and the organic layers were combined, dried (Na₂SO₄), and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with 0-30% (3:1 EtOAc:EtOH)/DCM to afford (1R,2S)-1-methoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide 103.0 (114 mg, 0.465 mmol, 63.0% yield) as a white solid. (contained ˜15% other diastereomer). ¹H NMR (300 MHz, CDCl₃) δ 8.63 (s, 2H), 5.10 (d, J=3.3 Hz, 1H), 4.78 (br. s., 2H), 3.74 (qd, J=7.1, 3.3 Hz, 1H), 3.51 (s, 3H), 2.36 (s, 3H), 1.33 (d, J=7.1 Hz, 3H). LCMS (ESI pos.) m/z: 246.1 (M+H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 103.0 using the known starting material as described.

Table 21 Example Reagents Structure, Name and Data

TABLE 21 Example Reagents Structure, Name and Data 103.1 2-bromo-5-methylpyrazine (NOWA pharmaceuticals).

LCMS-ESI (pos.) m/z: 246.2 (M + H)⁺. 103.2 2-chloro-5-fluoropyrimidine (Oakwood).

LCMS-ESI (pos.) m/z: 250.1 (M + H)⁺. 103.3 2,5-dichloropyrimidine (Oakwood).

LCMS-ESI (pos.) m/z: 265.9 (M + H)⁺. 103.4 2-chloropyrimidine (Acros Organics).

LCMS-ESI (pos.) m/z: 232.0 (M + H)⁺. 103.5 2-chloro-5-fluoropyrimidine (Oakwood). EtOTf used in place of MeOTf in Example 103.05.

LCMS-ESI (pos.) m/z: 264.0 (M + H)⁺. 103.6 2-chloro-5-fluoropyrimidine (Oakwood). TBSOTf used in place of MeOTf in Example 103.05.

LCMS-ESI (pos.) m/z: 350.1 (M + H)⁺. 103.7 2,5-dichloropyrimidine (Oakwood), EtOTf used in place of MeOTf in Example 103.05.

LCMS-ESI (pos.) m/z: 279.9.

Example 103.8: Preparation of (1R,2S)-1-methoxy-1-(5-methoxypyrimidin-2-yl) propane-2-sulfonamide

(1R,2S)-1-Methoxy-1-(5-methoxypyrimidin-2-yl)propane-2-sulfonamide, Example 103.8

This compound was obtained as a by-product of the synthesis of (1R,2S)-1-methoxy-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide (Example 103.2) during step 103.07 and isolated in the final step of the synthesis of Example 103.2 to give the title compound 103.8 (240 mg, 10.2% yield) as a white solid. ¹H NMR (CDCl₃) δ: 8.46 (s, 2H), 5.11 (d, J=3.4 Hz, 1H), 4.77 (br. s, 2H), 3.97 (s, 3H), 3.67-3.77 (m, 1H), 3.50 (s, 3H), 1.35 (d, J=7.0 Hz, 3H). LCMS-ESI (pos.) m/z: 284.1 (M+Na)⁺.

Example 104.0. Preparation of (1S,2S)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

5-Methylpyrimidine-2-carbonitrile, Example 104.01

A solution of 2-chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5 L) was degassed with N₂ for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd₂(dba)₃ (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)₂ (685 g, 5834 mmol, 1.5 equiv) was next added, and the reaction mixture was heated at 100° C. for 16 h. The reaction was then quenched with water (5 L) and stirred for 10 min. The reaction mixture was then filtered through Celite® filter aid. The filtrate was diluted with water (4 L) and extracted with EtOAc (2×4 L). The combined organic layers were washed with brine (4 L), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10% EtOAc in hexanes to obtain Example 104.01 (330 g, 71%) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 2H), 2.39 (s, 3H).

(R)—N,N-Bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide and (S)—N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide, Example 104.2

A solution of Example 100.0 (293 g, 839 mmol, 2.0 equiv) in THF (2 L) was added isopropylmagnesium chloride (420 mL, 839 mmol, 2.0 equiv, 2.0 M in diethyl ether) at 0° C. The reaction mixture was stirred at 25° C. for 3 h. To the reaction mixture was added 5-methylpyrimidine-2-carbonitrile (104.01, 50 g, 420 mmol, 1.0 equiv) in THF (100 mL) at 0° C., and the resulting mixture was stirred at RT for 2 h. The reaction was then quenched 1.5 N HCl (500 mL) and water (2 L) and then stirred for 10 min. The mixture was extracted with EtOAc (2×1000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na₂SO₄ and filtered. The organic layer was concentrated under reduced pressure to give the initial compound which was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexanes as eluent to obtain Example 104.2 (60 g, 30% yield) as a brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 2H), 7.15-7.09 (m, 4H), 6.85-6.80 (m, 4H), 4.34-4.18 (m, 5H), 3.71 (m, 6H), 2.39 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). LCMS (ESI pos.) m/z: (M+H)+: 470.0.

(E)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)prop-1-ene-2-sulfonamide, Example 104.3

A solution of Example 104.2 (120 g, 256 mmol, 1.0 equiv) in DMF (1.2 L) was added 2-iodopropane (129 mL, 1278 mmol, 5.0 equiv) and potassium carbonate (70.6 g, 511 mmol, 2.0 equiv). The reaction mixture was stirred at 60° C. for 14 h. The reaction was then quenched with water (1 L), stirred for 10 min, and extracted with EtOAc (2×1 L). The combined organic layers were washed with brine (1 L), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the initial material. The initial product was purified by column chromatography using silica gel (100-200 mesh) and 0-50% EtOAc in hexanes as eluent to obtain Example 104.3 (75 g, 57.4% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 2H), 7.09 (d, J=8.3 Hz, 4H), 6.86 (d, J=8.3 Hz, 4H), 4.16 (s, 4H), 3.73 (s, 3H), 3.73 (s, 3H), 3.71-3.67 (m, 1H), 2.31 (s, 3H), 1.87 (s, 3H), 1.19-1.16 (m, 6H). LCMS (ESI pos.) m/z: (M+H)+: 512.1.

(1S,2R)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 104.4

To a solution of Example 104.3 (180 g, 352 mmol, 1.0 equiv) in MeOH (1.8 L) were added zinc triflate (256 g, 704 mmol, 2.0 equiv) and (S)—RuCl[(p-cymene(BINAP)]C₁ (6.54 g, 7.04 mmol, 0.02 equiv). The resulting mixture was heated at 60° C. under H₂ pressure (60 psi) for 16 h. The reaction mixture was then concentrated under reduced pressure to obtain the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-50% EtOAc in DCM as eluent to obtain Example 104.4 (140 g, 77%, 92% ee) as off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 2H), 7.25-7.15 (m, 4H), 6.95-6.75 (m, 4H), 4.82 (dd, J=7.8, 1.8 Hz, 1H), 4.39 (d, J=15.6 Hz, 2H), 4.13 (d, J=15.7 Hz, 2H), 3.82 (qd, J=8.5, 7.9, 6.0 Hz, 1H), 3.65 (app s, 6H), 3.41-3.35 (m, 1H), 2.27 (s, 3H), 1.12 (dd, J=6.2, 1.8 Hz, 3H), 1.02 (dd, J=7.1, 2.0 Hz, 3H), 0.96 (dd, J=6.3, 1.8 Hz, 3H). LCMS (ESI pos.) m/z: (M+H)⁺: 514.2.

(1S,2S)-1-Isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 104.0

To a solution of Example 104.4 (140.0 g, 273 mmol, 1.0 equiv) in DCM (500 mL) was added TFA (250 mL) at 0° C. The reaction mixture was then stirred at RT for 16 h. The reaction mixture was then concentrated under reduced pressure to obtain the initial material which was dissolved in DCM (1 L) and washed with saturated aqueous NaHCO₃ solution (1 L). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain the initial material which was further purified by column chromatography using silica gel (60-120 mesh) and 0-2% MeOH in DCM to obtain Example 104.0 (72 g, 97% yield, 90% ee) as an off white solid. Example 104.0 (72 g, 90% ee) was suspended in IPA (500 mL) and heated to 70° C. until the mixture become homogeneous. Once the solution became homogeneous, the mixture was cooled to RT overnight. The white solid thus obtained was filtered and dried under vacuum providing Example 104.0 (30 g, >99%). The mother liquor was concentrated, and the solid obtained was recrystallized again following the same procedure. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, J=2.3 Hz, 2H), 6.45 (d, J=2.4 Hz, 2H), 4.68 (dd, J=8.8, 2.5 Hz, 1H), 3.59-3.52 (m, 1H), 3.48 (ddd, J=9.7, 7.4, 4.9 Hz, 1H), 2.29 (d, J=2.6 Hz, 3H), 1.13 (dd, J=6.1, 2.5 Hz, 3H), 0.93 (dd, J=7.1, 2.5 Hz, 3H), 0.88 (dd, J=6.3, 2.5 Hz, 3H). LCMS (ESI pos.) m/z: (M+H)+: 274.1.

The compounds in the following table were synthesized following the procedure in Example 104.0 using the known starting material as described.

TABLE 22 Example Reagents Structure, Name and Data 104.1 2-chloro-5-chloro- pyrimidine.

LCMS-ESI (pos.) m/z: 294.2, 296.2 (M + H)⁺.

Example 105.0. Preparation of (2S,3R)-3-(5-chloropyridin-2-yl)butane-2-sulfonamide

(2S,3R)-3-(5-Chloropyridin-2-yl)butane-2-sulfonamide, Example 105.0

To a solution of (E)-2-(5-chloropyridin-2-yl)ethenesulfonamide (10 g, 40.5 mmol) in MeOH (100 mL) was added zinc trifluoromethanesulfonate (2.95 g, 8.11 mmol), bis(1,5-cyclooctadiene)rhodium(I) tetrafluroborate (0.329 g, 0.811 mmol) and (S)-1-[(R)-2-(di-1-naphthylphosphino)ferrocenyl]-ethyl-di-tert-butylphosphine (0.651 g, 1.01 mmol). The reaction mixture was degassed with argon and hydrogen three times followed by hydrogen pressure (50 Psi) in a 200 mL Mini-clave at RT for 16 h followed by heating at 65° C. for 16 h. TLC indicated completion of reaction. The reaction product was concentrated under reduced pressure, and the product thus obtained was purified by column chromatography (silica gel 60-120 mesh) using 40-45% of EtOAc in petroleum ether as an eluent to obtain the desired product (2S,3R)-3-(5-chloropyridin-2-yl)butane-2-sulfonamide (Example 105.0, 9 g, 36.2 mmol, 89%) as a brownish solid in 82% ee. Recrystallization from i-PrOH yielded >97% ee material. 1H NMR (400 MHz, DMSO-d₆) δ 1.19 (d, J=7.05 Hz, 3H) 1.29 (d, J=7.05 Hz, 3H) 3.46 (qd, J=7.08, 3.84 Hz, 1H) 3.63 (qd, J=7.08, 3.84 Hz, 1H) 6.82 (s, 2H) 7.36 (d, J=8.50 Hz, 1H) 7.88 (dd, J=8.50, 2.70 Hz, 1H) 8.56 (d, J=2.28 Hz, 1H). LCMS-ESI (pos.) m/z: 249.0 (M+H)⁺.

Example 106.0. Preparation of (1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide

5-Methylpyrazine-2-carbaldehyde, Example 106.1

A solution of lithium aluminium hydride (164.0 mL, 0.164 mol, 1.0 M in THF, 0.5 equiv.) was added to a suspension of methyl 5-methylpyrazine-2-carboxylate (50 g, 0.328 mol, 1.0 equiv.) in anhydrous THF (750 mL) at −78° C. (The internal temperature was kept below −72° C. during the addition of lithium aluminium hydride). Upon completion of addition, the reaction mixture was left, to stir at −78° C. for a further 20 min and was then quenched with glacial AcOH (50.0 mL) at the same temperature. The resulting mixture was warmed to RT and the volatiles were removed by evaporation under pressure. The residue was dissolved in 1.5 N HCl (500 mL) and extracted with DCM (2×2 L). The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution (2×500 mL), (Note: no product observed in HCl or aqueous sodium hydrogen carbonate solution) dried over anhydrous Na₂SO₄, and concentrated in vacuo, to yield the initial product as a brown oil. The residue was purified by column chromatography (silica gel 60-120 mesh) eluting with a gradient of 10% EtOAc in petroleum ether to provide the title compound as a pale yellow liquid (21.3 g, 53%). TLC Info: (9.0/1.0 Petroleum ether/EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 10.14 (s, 1H), 9.07 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.4 Hz, 1H), and 2.70 (s, 3H). LCMS (ESI positive ion) m/z: 123 (M+H)⁺.

(1R,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1S,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide, Example 106.2

To a solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (Example 100.0, 73.13 g, 0.21 mol, 1.2 equiv.) in anhydrous THF (600 mL) at −78° C. was added n-butyl lithium (83.71 mL, 0.209 mol, 2.5 M solution in hexanes, 1.2 equiv.) slowly via additional funnel, and the resulting mixture was stirred for 10 min. Next, a solution of 5-methylpyrazine-2-carbaldehyde (Example 106.1, 21.3 g, 0.17 mol, 1.0 equiv.) in anhydrous THF (150 mL) was added, and the mixture was stirred at the same temperature for 45 min and then stirred and allowed to warm to RT for 2 h. The reaction mixture was quenched by addition of aqueous ammonium chloride (200 mL) and extracted with EtOAc (2×2 L). The combined organic layers were washed with brine (2×500 mL) (Note: no product was observed in the ammonium chloride or brine layer). After drying over anhydrous Na₂SO₄, the filtrate was concentrated in vacuo, to afford the initial product as an oil. The oil thus obtained was purified by flash column chromatography (silica gel, 230-400 mesh) to afford the two isomers. The faster moving isomer (32 g as a white solid) was obtained from the column with a gradient of 10% to 30% EtOAc in petroleum ether. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=1.5 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 7.22-7.11 (m, 4H), 6.90-6.80 (m, 4H), 6.10 (d, J=5.9 Hz, 1H), 5.29 (dd, J=5.9, 2.2 Hz, 1H), 4.36-4.16 (m, 4H), 3.73 (app s, 6H), 3.70-3.66 (m, 1H) 2.50 (merged with solvent peak, 3H) and 1.10 (d, J=7.0 Hz, 3H). LCMS (ESI positive ion) m/z: 472.4 (M+H)⁺.

(1S,2S)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methyl-pyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methyl-pyrazin-2-yl)propane-2-sulfonamide, Example 28.3

Further elution of the mixture with a gradient of 30% to 35% EtOAc in petroleum ether yielded Example 106.3 (16 g, pale yellow gummy liquid). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (d, J=1.6 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 7.25-7.12 (m, 4H), 6.93-6.82 (m, 4H), 5.17 (d, J=7.1 Hz, 1H), 4.47 (d, J=15.2 Hz, 3H), 4.14 (d, J=15.4 Hz, 2H), 3.82 (s, 3H), 3.82 (s, 3H), 3.66-3.61 (m, 1H), 2.60 (d, J=2.0 Hz, 3H), and 1.08 (dd, J=7.2, 2.1 Hz, 3H). LCMS (ESI pos.) m/z: 472.4 (M+H)⁺.

(1S,2S)-1-Isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide, Example 106.4

To a flask containing (1S,2S)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide (Example 106.3, 4.16 g, 8.81 mmol) and isopropyl iodide (12.3 mL, 123 mmol) in anhydrous toluene (35 mL) was added silver(I) oxide (4.17 g, 18.0 mmol) carefully in portions. Upon complete addition of silver oxide, the reaction was protected from light and heated to an internal temperature of 72° C. After 60 h, the mixture was cooled to RT and then filtered through a Chemglass disposable filter that was rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The dark brown residue was loaded onto a silica gel column (10-55% EtOAc in heptanes). Fractions containing the product were combined and then concentrated under reduced pressure to afford (1S,2S)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-isopropoxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide (Example 106.4, 1.52 g, 2.97 mmol, 34% yield) a dark brown oil that was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (d, J=1.5 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 7.20-7.15 (m, 4H), 6.89-6.85 (m, 4H), 4.81 (d, J=7.0 Hz, 1H), 4.35-4.29 (m, 2H), 4.20-4.13 (m, 2H), 3.76-3.71 (m, 7H), 3.39 (quin, J=6.1 Hz, 1H), 2.51 (s, 3H), 1.13 (d, J=6.0 Hz, 3H), 1.05 (d, J=7.3 Hz, 3H), 0.99 (d, J=6.2 Hz, 3H). LCMS (ESI pos.) m/z: 514.0 (M+H)⁺.

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide, Example 106.5. Anisole (1.3 mL, 11.9 mmol) was added to a flask containing Example 106.4 (1.5 g, 3 mmol) and DCM (7.5 mL). The homogeneous solution was cooled in an ice-water bath. After 15 min, TFA (7.6 mL, 99 mmol) was added dropwise to the reaction solution. Upon complete addition of TFA, the reaction was allowed to warm to 23° C. After 20 h, the brownish reaction solution was concentrated under reduced pressure. The residue was loaded onto a silica gel column (15-85% EtOAc in heptanes). Fractions containing the product were concentrated under reduced pressure to afford (1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide (Example 106.5, 714 mg, 2.6 mmol, 88% yield) as an off white solid. LCMS (ESI pos.) m/z: 274.0 (M+H)⁺.

Preparation of (1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide, Example 106.6

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide and (1R,2R)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide (Example 106.5, 714 mg, 2.6 mmol) was purified by preparative SFC using the following method. Column: IC (2×25 cm) Mobile Phase: 70:30 (A:B) A: Liquid CO₂, B: IPA. This provided peak 1 as Example 106.6 (293 mg, 1.07 mmol, 36% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.56-3.45 (m, 2H), 1.15 (d, J=6.0 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.96 (d, J=6.2 Hz, 3H). (Obscured CH₃ in DMSO peak). LCMS (ESI pos.) m/z: 274.2 (M+H)⁺.

(1R,2R)-1-Isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide or (1S,2S)-1-isopropoxy-1-(5-methylpyrazin-2-yl)propane-2-sulfonamide, Example 106.0

Further elution under the conditions described in Example 106.5 delivered Second eluting peak as Example 106.0, 303 mg, 1.11 mmol, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=1.5 Hz, 1H), 8.53 (d, J=1.0 Hz, 1H), 6.52 (s, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.58-3.44 (m, 2H), 1.27-1.14 (m, 3H), 1.05 (d, J=7.0 Hz, 3H), 1.00-0.91 (m, 3H). (Obscured CH₃ in DMSO peak). LCMS (ESI pos.) m/z: 274.2 (M+H)⁺.

Example 107.0. Preparation of (2R,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamide and (2R,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamide and (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamide and (2S,3S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrazinyl)-2-butanesulfonamide

(2R,3R)-3-(5-Methoxypyrazin-2-yl)butane-2-sulfonamide and (2R,3S)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and (2S,3R)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide and (2S,3S)-3-(5-methoxypyrazin-2-yl)butane-2-sulfonamide, Example 107.0

Example 107.0 was synthesized following the procedure in Example 105.0 using 2-bromo-5-methoxypyrazine (commercially available from Ark Pharm, Inc.). LCMS-ESI (pos.) m/z: 246.2 (M+H)⁺.

Example 108.0. Preparation of (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanesulfonamide or (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-((2R)-1,4-dioxan-2-yl)-4H-1,2,4-triazol-3-yl)-3-(5-methoxy-2-pyrimidinyl)-2-butanesulfonamide

(2S,3R)-3-(5-Methoxypyrimidin-2-yl)butane-2-sulfonamide, Example 108.1

A round bottom flask was charged with (2S,3R)-3-(5-fluoropyrimidin-2-yl)butane-2-sulfonamide (575 mg, 2.47 mmol, Example 56.5), MeOH (7 mL), and potassium carbonate (679 mg, 4.91 mmol). The reaction was stirred at RT. After 48 h, the reaction was heated to 50° C. and stirred for 24 h. The temperature was then raised to 65° C., and the reaction was stirred for 48 h. LCMS-ESI showed the reaction was 75% complete. The reaction was allowed to cool to RT and filtered. The solids were rinsed with MeOH (2×5 mL). The filtrate was concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a RediSep® pre-packed silica gel column, eluting with 0-40% EtOAc:EtOH (3:1) in heptanes. The chromatography solvents were contaminated with water. The organic layer from several fractions were concentrated in vacuo to give a mixture of starting material and the title compound (56 mg, 0.23 mmol, 9% yield) as an off-white solid. The fractions with a water layer were combined and the aqueous layer was saturated with NaCl and extracted with CHCl₃:IPA (9:1, 3×15 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give more title compound (114 mg). The material was carried forward as is. LCMS-ESI (pos.) m/z: 246.1 (M+H)⁺.

Example 109.3. Preparation of (3S,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide

5-Methoxypyridine-3-sulfonamide, Example 109.1

The reaction mixture of 5-methoxypyridine-3-sulfonyl chloride (commercially available from Enamine, Kiev, Ukraine) (1.0 g, 4.82 mmol) and ammonia, (0.5 M solution in 1,4-dioxane. 96 mL, 48.2 mmol) was stirred at 0° C. to RT for 30 min. LCMS indicated the reaction was complete. The reaction was filtered and the filter cake was rinsed with dioxane. The combined solution was concentrated in vacuo to give the title compound (0.91 g, 100% yield) as a light yellow foam which was used directly in the next step without purification. LCMS-ESI (pos.) m/z: 189.2 (M+H)⁺.

(3S,5R)-5-Methoxypiperidine-3-sulfonamide acetate and (3R,5S)-5-methoxypiperidine-3-sulfonamide acetate, Example 109.2

A mixture of 5-methoxypyridine-3-sulfonamide (0.9 g, 4.78 mmol) in AcOH (31.9 mL) was bubbled with argon gas for 2 min before platinum (iv) oxide ((1.09 g, 4.78 mmol) was added under an argon stream. The reaction mixture was then stirred at RT under 45 psi of hydrogen gas for 38 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.22 g, 100% yield) as a light yellow foam, which was used as such for the next step. LCMS-ESI (pos.) m/z: 195.2 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.3

To a 40 mL vial (w/pressure release septa) was added 5-methoxypiperidine-3-sulfonamide acetate, (109.2, 2.45 g, 9.62 mmol), N-ethyl-N-isopropylpropan-2-amine (16.75 mL, 96 mmol) and 2-chloro-5-fluoropyrimidine (6.37 g, 48.1 mmol) in DMSO (48 mL). The reaction mixture was stirred at 100° C. for 23 h. LCMS indicated formation of the desired product. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with saturated aqueous NaCl, brine and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to give the initial material as an orange oil. The initial material was absorbed onto a plug of silica gel and purified by chromatography through RediSep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% 1/3 EtOH/EtOAc in heptane to provide the title compound, 109.3 (0.51 g, 18% yield) as white solid, LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide and (3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.4

Further elution under the conditions described in Example 109.3 delivered 109.4 (0.24 g, 0.832 mmol, 8.65% yield) as a light yellow solid. LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.5

Example 109.5 was obtained by chiral separation of 109.3 on SFC: Chiralpak AD-H, 30% MeOH/CO₂, with 0.2% DEA. Example 109.5 was the earlier peak to elute on the Chiralpak AD-H column. ¹H NMR (400 MHz, CD₃OD) δ 1.65 (td, J=12.28, 10.88 Hz, 1H) 2.57-2.72 (m, 2H) 2.98 (dd, J=13.06, 11.40 Hz, 1H) 3.14 (ddt, 1H) 3.27-3.36 (m, 1H) 3.45 (s, 3H) 4.97 (ddt, 1H) 5.17 (ddt, 1H) 8.32 (d, J=0.62 Hz, 2H). LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3S,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or (3R,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.6

Further elution under the conditions described in Example 109.5 delivered Example 109.6. ¹H NMR (400 MHz, CD₃OD) δ 1.65 (td, J=12.28, 10.88 Hz, 1H) 2.57-2.71 (m, 2H) 2.94-3.04 (m, 1H) 3.14 (ddt, 1H) 3.31-3.36 (m, 1H) 3.45 (s, 3H) 4.97 (ddt, 1H) 5.17 (ddt, 1H) 8.32 (s, 2H). LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3S,5S)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or (3R,5R)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.7

Example 109.7 was obtained by chiral separation of 109.3 on SFC: Chiralpak AD-H, 25% MeOH/CO₂, with 0.2% DEA. Example 109.7 was the earlier peak to elute on Chiralpak AD-H column. ¹H NMR (400 MHz, CD₃OD) δ 1.98 (ddd, J=13.42, 12.39, 3.01 Hz, 1H) 2.41-2.51 (m, 1H) 2.98 (dd, J=14.31, 1.66 Hz, 1H) 3.10 (dd, J=13.06, 11.20 Hz, 1H) 3.29-3.36 (m, 1H) 3.32 (s, 3H) 3.66-3.71 (m, 1H) 4.98 (dq, J=14.38, 2.19 Hz, 1H) 5.18 (ddt, 1H) 8.29 (d, J=0.83 Hz, 2H) LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

(3R,5R)-1-(5-Fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide or (3S,5S)-1-(5-fluoropyrimidin-2-yl)-5-methoxypiperidine-3-sulfonamide, Example 109.8

Further elution under the conditions described in Example 109.6 delivered Example 109.8. ¹H NMR (400 MHz, CD₃OD) δ 1.96 (ddd, J=13.39, 12.45, 2.93 Hz, 1H) 2.44 (dt, J=13.48, 1.89 Hz, 1H) 2.97 (dd, J=14.33, 1.58 Hz, 1H) 3.08 (dd, J=13.01, 11.14 Hz, 1H) 3.28-3.35 (m, 1H) 3.32 (s, 3H) 3.60-3.72 (m, 1H) 4.87-5.00 (m, 1H) 5.16 (dt, J=13.02, 1.91 Hz, 1H) 8.27 (d, J=0.67 Hz, 2H). LCMS-ESI (pos.) m/z: 291.0 (M+H)⁺.

Example 104.5. Preparation of (1R,2R)-1-hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

N-Methoxy-N,5-dimethylpyrimidine-2-carboxamide, Example 104.21

To a solution of 5-methylpyrimidine-2-carboxylic acid (1 g, 7.24 mmol) in DMF (72.4 mL) was added 5-methylpyrimidine-2-carboxylic acid (1 g, 7.24 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.777 g, 7.96 mmol). The mixture was cooled to 0° C. and 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in EtOAc (9.21 mL, 14.48 mmol) was added dropwise. The mixture was allowed to warm to RT overnight after which LCMS indicated complete conversion to product. The mixture was diluted with water, extracted with CHC₃:IPA (3:1) and washed with brine and then NaHCO₃. The mixture was dried over Na₂SO₄, concentrated in vacuo and purified by silica gelchromatograph (0-100% heptanes:EtOAc) to yield N-methoxy-N,5-dimethylpyrimidine-2-carboxamide (0.7 g, 3.86 mmol, 53.4% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.61-8.69 (m, 2H) 3.61-3.79 (m, 3H) 3.27-3.47 (m, 3H) 2.34-2.45 (m, 3H). LCMS-ESI (pos.) m/z: 182.2 (M+H)⁺.

(R)—N,N-Bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide and (S)—N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)-1-oxopropane-2-sulfonamide, Example 104.2

A solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (azeotroped three times with toluene before use) (Example 100.0, 0.771 g, 2.208 mmol) was dissolved in THF (3.68 mL) and cooled to −78° C. using a dry ice acetone bath (internal reaction temperature/bath temperature not monitored). To this mixture was added a solution of n-butyllithium (0.883 mL, 2.21 mmol, 2.5M in hexanes). The reaction turned pink immediately and then slowly faded to yellow upon stirring at −78° C. for 30 min. This solution was then added quickly to a solution of N-methoxy-N,5-dimethylpyrimidine-2-carboxamide (Example 104.21, 0.2 g, 1.104 mmol) in THF (0.5 mL) at RT. The reaction was stirred at RT for −20 min after which LCMS indicated complete consumption of weinreb amide and conversion to product. The reaction was quenched by addition to separation funnel that contained 1M HCl (˜15 mL). The mixture was extracted with DCM, (aqueous layer was checked for product by LCMS) dried over Na₂SO₄ and concentrated in vacuo. The mixture was then purified by silica gel chromatography 0-100% EtOAc:Heptanes to yield 104.2 (0.36 g, 0.767 mmol, 69.5% yield)¹H NMR (500 MHz, DMSO-d₆) δ 8.86-8.93 (m, 2H) 7.06-7.15 (m, 4H) 6.79-6.87 (m, 4H) 5.87-5.95 (m, 1H) 4.20-4.34 (m, 4H) 3.67-3.73 (m, 6H) 2.38-2.42 (m, 3H) 1.46-1.55 (m, 3H). LCMS-ESI (pos.) m/z: 470.0 (M+H)⁺.

(1R,2R)-1-Hydroxy-N,N-bis(4-methoxybenzyl)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 104.5

To a solution of Example 104.2 (1.0 g, 2.13 mmol) in DMF (22.18 mL) was added (N-((1S,2S)-1,2-diphenyl-2-((3-phenylpropyl)amino)ethyl)-4-methylphenylsulfonamido)ruthenium(II) chloride (9.91 mg, 0.016 mmol). The mixture was then degassed by placing under vacuum and backfilling with N₂ three times. To this mixture was added a solution of HCOOH:Et₃N (5:2 v/v) (0.55 mL) and the reaction stirred at RT for 12 hrs after which LCMS indicated complete conversion to product and 7:1 d.r. (syn:anti). The mixture was then washed with 5% LiCl (aq) and extracted with DCM and then CHCl₃:IPA (3:1). The organic layers were dried over Na₂SO₄ and concnentrated in vacuo. The mixture was loaded directly onto a silica gel column and purified using a gradient of 0-100% heptanes:EtOAc to yield the title compound (0.77 g, 1.63 mmol, 77% yield) as an off white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.85-8.93 (m, 2H) 7.08-7.15 (m, 4H) 6.78-6.86 (m, 4H) 5.86-5.96 (m, 1H) 4.20-4.35 (m, 4H) 3.68-3.75 (m, 6H) 3.28-3.34 (m, 2H) 2.37-2.42 (m, 3H) 1.47-1.54 (m, 3H) LCMS-ESI (pos.) m/z: 572.2 (M+H)⁺.

Example 111.0. Preparation of (S)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Fluoro-2-(prop-1-en-1-yl)pyrimidine and (Z)-5-fluoro-2-(prop-1-en-1-yl)pyrimidine, Example 111.1

Iodine (1-2 crystals) was added to magnesium turnings (9.0 g, 371.9 mmol) under anhydrous conditions. The mixture was heated at 60° C. for 5 min under reduced pressure to activate the magnesium. The flask was cooled to RT and THF (370 mL) was added. The resulting mixture was heated to 65° C., (Z/E)-1-bromo-1-propene (45 g, 371.9 mmol) was added dropwise, and the mixture was then stirred at 65° C. for 2 h under a nitrogen atmosphere. Thereafter, the mixture was cooled to RT and transferred to an ice bath. Zinc chloride (1.0 M in diethyl ether, 283 mL, 283 mmol) was then added dropwise over 10 min. The internal temperature of the reaction was kept at −10-15° C. during the addition, and the resulting organozinc reagent was stirred at RT for 45 min. In a separate round bottomed flask, a solution of 2-chloro-5-fluoropyrimidine (commercially available from Novochemy, Jupiter, Fla., USA) (25 g, 189 mmol), S-phos (7.7 g, 18.8 mmol) and palladium (II) acetate (2.1 g, 9.4 mmol) in THF (38 mL) was degassed with nitrogen gas for 5 min. The organozinc reagent was then added dropwise. The resulting mixture was heated at 60° C. for 12 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with water (50 mL) and acidified with 1N hydrochloric acid (700 mL, pH ˜2). The mixture was extracted with diethyl ether (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure at 20° C. to a volume of approximately 50 mL containing 111.1, which was used as such in the next step.

(S)-1-(5-Fluoropyrimidin-2-yl)propane-2-sulfonic acid and (R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonic acid, Example 111.2

To a solution of 111.1 (188.6 mmol) in THF (50 mL) was added an aqueous solution of sodium bisulfite (19.6 g, 188.6 mmol in 100 mL of H₂O). The reaction mixture was stirred at RT for 20 h. Once the reaction was complete (monitored by TLC), the mixture was acidified to approximately pH 1 with concentrated HCl (10 mL). The aqueous layer was then concentrated under reduced pressure to furnish the initial product which was suspended in EtOH (250 mL). The product thus obtained was heated to reflux, filtered hot, and rinsed with hot EtOH (100 mL). The filtrate was concentrated under reduced pressure to give a brown solid, which was recrystallized from IPA (50 mL) to afford 111.2 (20 g, 48% yield) as a brown solid. ¹H NMR (400 MHz, D₂O) δ 8.69 (s, 2H), 3.47 (td, J=9.8, 8.2, 4.0 Hz, 2H), 3.06 (dd, J=16.1, 10.2 Hz, 1H), 1.24 (d, J=6.5 Hz, 3H). LCMS-ESI (neg.) m/z: 118.9 (M−H)⁻.

(S)-1-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide and (R)-1-(5-fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide, Example 111.3

A 250 mL 3 necked round-bottomed flask equipped with a mechanical stirrer, N₂ inlet, a condenser, and a temperature probe was charged with Example 111.2 (15 g, 68.1 mmol) and thionyl chloride (49.7 mL, 681 mmol). The mixture was heated to 60° C. After 1.5 h, LCMS showed full conversion of the starting material. The reaction mixture was concentrated to remove additional thionyl chloride and azeotroped with cyclpropylmethyl ether (50 mL×2). The resulting intermediate was suspended in DCM (100 mL) and 4-methoxybenzylamine (26.5 mL, 204 mmol) and TEA (47.4 mL, 341 mmol) were added. The mixture was stirred at RT for 18 hours. Next, the reaction was diluted with DCM (100 mL) and brine (50 mL). The organic layer was separated and the initial material was purified by flash chromatography: (DCM/EtOAc=10:0 to 8:2) to afford ˜20 g of an oil.

(S)-1-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide, Example 111.4

A chiral SFC purification of Example 111.3 was performed. Preparative SFC method: Column: Chiralpak AS-H (5×25 cm), Mobile Phase: 75:25 (A:B), A: Liquid CO₂, B: MeOH w/0.2% DEA, Flow Rate: 350 mL/min, 223 nm, 100 bar inlet pressure and provided two peaks of >99.5% ee: The first eluting peak was assigned Example 111.4. LCMS-ESI (pos.) m/z: 340.1 (M+H)⁺.

(S)-1-(5-Fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)-N-(4-methoxybenzyl)propane-2-sulfonamide, Example 111.5

The second eluting peak described in the conditions described in Example 111.4 was assigned Example 111.5. LCMS-ESI (pos.) m/z: 340.1 (M+H)⁺.

(S)-1-(5-Fluoropyrimidin-2-yl)propane-2-sulfonamide OR (R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide, Example 111.6

To a 1 L 3 necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet, and a temperature probe was charged Example 111.4 (18 g, 53.0 mmol), DCM (180 mL), anisole, anhydrous (17.29 mL, 159 mmol) and TFA (270 mL). The mixture was stirred at RT. After 24 hours the reaction was concentrated, azeotroped with EtOAc, loaded on silica gel, and purified by column (Heptanes:EtOAc=10:0 to 0:10) to afford Example 111.6 (11.5 g, 52.5 mmol, 99% yield). LCMS-ESI (pos.) m/z: 220.2 (M+H)⁺.

Example 111.0. Preparation (S)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide or (R)-1-(5-fluoropyrimidin-2-yl)propane-2-sulfonamide

The title compound was synthesized using the method described for the synthesis of Example 111.6, employing Example 111.5. LCMS-ESI (pos.) m/z: 220.2 (M+H)⁺.

Example 112.0. Preparation of 2-(2-cyano-4-fluorophenyl)ethanesulfonamide

Methyl 2-(2-bromo-4-fluorophenyl) acetate, Example 112.1

To a solution of 2-bromo-4-fluorophenyl acetic acid (commercially available from Combi-Blocks Inc., San Diego, Calif., USA) (25.0 g, 0.11 mol) in MeOH (100 mL) was added thionyl chloride (23.5 mL, 0.32 mol) dropwise at 0° C. The resulting mixture was then heated at 80° C. for 16 h. The mixture was cooled to RT and the volatiles were removed under vacuum. The material thus obtained was diluted with DCM and washed with an aqueous solution of sodium bicarbonate and water. The organic layers were dried over sodium sulfate, filtered and evaporated to afford Example 112.1 (26 g, 100% yield), which was used as such in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (dd, J=8.6, 2.6 Hz, 1H), 7.47 (dd, J=8.5, 6.2 Hz, 1H), 7.25 (td, J=8.5, 2.7 Hz, 1H), 3.82 (s, 2H), 3.63 (s, 3H).

Methyl 2-(2-cyano-4-fluorophenyl) acetate, Example 112.2

To a solution of 112.1 (8.0 g, 0.032 mol) in DMAc (60 mL) was added zinc cyanide (5.7 g, 0.049 mol). The flask was then degassed with argon and bis-(tri-tert-butylphosphine)palladium (1.7 g, 0.003 mol) was added. The resulting mixture was then heated at 110° C. for 18 h in a sealed tube. Thereafter, the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulphate and evaporated in vacuo. The product thus obtained was purified by silica gel chromatography (eluent: 20-25% EtOAc in hexanes) to obtain 112.2 (5.4 g, 86% yield) as a light brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.81 (m, 1H), 7.68-7.51 (m, 2H), 3.95 (s, 2H), 3.65 (s, 3H). LCMS-ESI (neg.) m/z: 192.2 (M−H)⁻.

5-Fluoro-2-(2-hydroxyethyl)benzonitrile, Example 112.3

To a solution of 112.2 (5.3 g, 0.027 mol) in THF (60 mL) at 0° C. was added LiBH₄ (1.20 g, 0.055 mol) portion-wise. The resulting mixture was stirred at 25° C. for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. and quenched with water. The solvent was evaporated to obtain the initial material which was further diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated in vacuo to obtain the product, which was further purified by silica gel chromatography (eluent: 15-20% EtOAc in hexanes) to obtain 112.3 (3.1 g, 67% yield) as a light brown liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.73 (m, 1H), 7.52 (dd, J=10.6, 8.0 Hz, 2H), 4.82 (t, J=5.2 Hz, 1H), 3.64 (dd, J=11.9, 6.5 Hz, 2H), 2.91 (t, J=6.6 Hz, 2H).

2-(2-Chloroethyl)-5-fluorobenzonitrile, Example 112.4

To a solution of 112.3 (3.0 g, 0.018 mol) in DCM (50 mL) was added thionyl chloride (6.6 mL, 0.091 mol) dropwise followed by DMF (4 drops) at 0° C. The resulting mixture was heated at 55° C. for 7 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to obtain the initial product, which was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and evaporated in vacuo to obtain 112.4 (3.0 g, 90% yield) as a brown liquid which was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.84 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.56-7.66 (m, 2H), 3.90-3.94 (t, J=6.8 Hz, 13.6 Hz, 2H), 3.22-3.25 (t, J=6.8 Hz, 13.2 Hz, 2H). LCMS-ESI (neg.) m/z: 182.0 (M−H)⁻.

Sodium 2-(2-cyano-4-fluorophenyl)ethanesulfonate, Example 112.5

To a solution of 112.4 (3.0 g, 0.016 mol) in H₂O (50 mL) at RT was added sodium sulfite (3.1 g, 0.024 mol). The reaction mixture was heated at reflux for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo to obtain the initial material, which was further stirred with EtOAc and filtered to obtain 112.5 (5.8 g) as an off-white solid, which was used for the next reaction without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.74-7.76 (dd, J=2 Hz, 8.4 Hz, 1H), 7.47-7.55 (m, 2H), 3.05-3.09 (t, J=8 Hz, 16.4 Hz, 2H), 2.69-2.74 (t, J=8.4 Hz, 16.4 Hz, 2H). LCMS-ESI (neg.) m/z: 228.0 (M−H)⁻.

2-(2-Cyano-4-fluorophenyl)ethanesulfonyl chloride, Example 112.6

To a solution of 112.5 (5.8 g) in benzene (50 mL) was added thionyl chloride (2.5 mL, 0.035 mol) dropwise followed by DMF (3 drops) at 0° C. The resulting mixture was heated to reflux for 16 h. After completion of the reaction (monitored by TLC), the mixture was cooled to RT, poured into ice water and extracted with EtOAc. The EtOAc layer was dried over Na₂SO₄, filtered and evaporated in vacuo to obtain 112.6 (3.4 g, 84% yield over two steps) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.38 (m, 2H), 7.33 (td, J=8.2, 2.7 Hz, 1H), 3.98 (dd, J=8.7, 6.7 Hz, 2H), 3.56-3.53 (m, 2H). LCMS-ESI (neg.) m/z: 245.9 (M−H)⁻.

2-(2-Cyano-4-fluorophenyl)ethanesulfonamide, Example 112.0

To a mixture of aqueous ammonia (10 mL, 77 mmol) and DCM (30 mL, 468 mmol) was added Example 112.6 (1.42 g, 5.73 mmol) in portions at RT. The reaction mixture was stirred at RT for 2 h. LCMS analysis indicated the reaction was complete. The mixture was neutralized by adding concentrated HCl solution, and then extracted with DCM. The extract was washed with water and saturated sodium bicarbonate solution twice, dried over Na₂SO₄ and concentrated in vacuo. The residue was dried to provide 112.0 (1.1 g, 84% yield) as a white solid. LCMS-ESI (pos.), m/z: 229.1 (M+H)⁺.

Example 113.0. Preparation of (1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide

(E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine, Example 113.1

To a solution of 2-chloro-5-methylpyrimidine (100.0 g, 778 mmol, 1.0 equiv, Angene) in 1,4-dioxane (1000 mL) and water (150 mL) was added potassium (E)-trifluoro(prop-1-en-1-yl)borate (127 g, 856 mmol, 1.1 equiv, Frontier), tricyclohexylphosphine (21.81 g, 78 mmol, 0.1 equiv, Spectrochem) and potassium phosphate tribasic (330 g, 1556 mmol, 2.5 equiv, Sigma). The resulting mixture was degassed with nitrogen for 20 min. Tris(dibenzylideneacetone) dipalladium (0) (35.6 g, 38.9 mmol, 0.05 equiv, Hindustan Platinum) was added to the reaction mixture which was degassed with nitrogen for additional 5 min. The resulting reaction mixture was heated at 100° C. for 16 h. The reaction mixture was cooled to RT diluted with EtOAc (2000 mL) and filtered through Celite® filter aid. The filtrate was partitioned between EtOAc (2000 mL) and water (2000 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the initial material which was further purified by column chromatography (silica gel: 60-120 mesh, elution: 0-5% EtOAc in hexane) to obtain (E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine (75 g, 71.9%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 2H), 7.05-6.96 (m, 1H), 6.47 (d, J=16 MHz, 1H), 2.22 (s, 3H), 1.90 (dd, J=2.7 Hz, 3H). LCMS (ESI+νe ion) m/z: [M+H]: 135.2.

(1R,2R)-1-(5-Methylpyrimidin-2-yl)propane-1,2-diol, Example 113.2

To a suspension of AD-Mix-3 (834 g, 596 mmol, 1 equiv), t-butanol (1200 mL), water (1200 mL) was added methane sulfonamide (56.7 g, 596 mmol, 1.0 equiv). The mixture was stirred at RT until clear (15 min) and then cooled to 0° C. (E)-5-Methyl-2-(prop-1-en-1-yl) pyrimidine (80 g, 596 mmol, 1.0 equiv) in t-BuOH (400 mL) was added, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the preciptates were washed with 10% MeOH in DCM (3×1000 mL). The organic layer was separated from the filtrate, and the aqueous layer was extracted with 10% MeOH in DCM (4×1500 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain the initial product which was further purified by column chromatography (silica gel 60-120 mesh) using 0-3% MeOH in DCM as an eluent to obtain the desired product 1-(5-methylpyrimidin-2-yl)propane-1,2-diol (70 g, 69.8% yield) as a brown oil with ˜87% ee. ¹H NMR (300 MHz, DMSO-d₆) δ 8.76-8.50 (m, 2H), 4.92 (dd, J=6.5, 1.4 Hz, 1H), 4.45 (dd, J=5.7, 1.4 Hz, 1H), 4.34 (ddd, J=6.4, 5.0, 1.3 Hz, 1H), 4.01-3.92 (m, 1H), 2.26 (d, J=1.3 Hz, 3H), 0.97 (dd, J=6.5, 1.3 Hz, 3H). LCMS (ESI+νe ion) m/z: [M+1]: 169.2.

5-Methyl-2-((2S,3R)-3-methyloxiran-2-yl)pyrimidine, Example 113.3

To a solution of (1R,2R)-1-(5-methylpyrimidin-2-yl)propane-1,2-diol (80.0 g, 476 mmol, 1.0 equiv) in DCM (800 mL) was added trimethyl orthoacetate (274 mL, 2140 mmol, 4.5 equiv, Spectrochem) slowly at RT under nitrogen atmosphere. The resulting reaction mixture was allowed to stir at RT under N₂ for 1 h and was then treated with chlorotrimethyl silane (274 mL, 2140 mmol, 4.5 equiv, Spectrochem). The reaction mixture was stirred at RT under N₂ for 24 h. The reaction was then concentrated under reduced pressure. The residue was dissolved in MeOH (400 mL) and treated with potassium carbonate (65.7 g, 476 mmol, 1 equiv) and stirred at RT under N₂ for 3 h. The resulting mixture was filtered and the filter cake was washed with DCM (2×500 mL). The combined filtrates were concentrated under reduced pressure. The initial material was purified by column chromatography (silica-gel 60-120 mesh, 25% to 30% EtOAc in hexane) to obtain 5-methyl-2-((2S, 3R)-3-methyloxiran-2-yl) pyrimidine (35 g, 49% yield) as a yellow oil. 25 g of starting material was recovered, which was again subjected for the reaction. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 2H), 3.74 (d, J=1.9 Hz, 1H), 3.43 (dt, J=6.5, 4.7 Hz, 1H), 2.26 (s, 3H), 1.39 (d, J=5.2 Hz, 3H). MS (ESI+νe ion) m/z: [M+1]: 151.2.

(1R,2S)-2-(Benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol, Example 113.4

To a solution of 5-methyl-2-((2S,3R)-3-methyloxiran-2-yl)pyrimidine (35 g, 233 mmol, 1.0 equiv) in DCM (350 mL) was added benzo[d]thiazole-2-thiol (39.0 g, 233 mmol, 1.0 equiv, combi block) and Ytterbium (III) trifluoromethanesulfonate (14.46 g, 23.31 mmol, 0.1 equiv, Combi Block). The reaction mixture was stirred at RT for 16 h. The reaction mixture was then concentrated under reduced pressure to obtain the initial material which was purified by column chromatography (silica-gel 60-120 mesh, 5% to 30% EtOAc in hexane) to obtain (1R,2S)-2-(benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol (50.0 g, 60.8% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 2H), 7.90 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.46 (m, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.87 (d, J=6.1 Hz, 1H), 4.96 (t, J=6.8 Hz, 1H), 4.61-4.57 (m, 1H), 2.25 (s, 3H), 1.35 (d, J=6.9 Hz, 3H). LCMS (ESI+νe ion) m/z: [M+H]: 318.2.

2-(((1R,2S)-1-((tert-Butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole, Example 113.5

To a solution of (1R,2S)-2-(benzo[d]thiazol-2-ylthio)-1-(5-methylpyrimidin-2-yl)propan-1-ol (120 g, 378 mmol, 1.0 equiv) in THF (1200 mL, 10.00 mL/g) was added potassium bis(trimethylsilyl)amide (454 mL, 454 mmol, 1.2 equiv) drop wise at −70° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 h. tert-Butyldimethylsilyl trifluoromethanesulfonate (191 mL, 832 mmol, 2.2 equiv) was added, and the reaction mixture was stirred for 30 min at −70° C. The completion of reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride (1000 mL) solution and extracted with EtOAc (2×1000 mL). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain the initial material which was purified by column chromatography (silica-gel 60-120 mesh, eluent: 5%-15% EtOAc in hexane) to obtain 2-(((1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propan-2-yl)thio)benzo[d]thiazole (124 g, 76%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 2H), 7.85 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.44-7.37 (m, 1H), 7.29 (d, J=8.1 Hz, 1H), 5.19 (d, J=6.1 Hz, 1H), 4.54 (p, J=6.8 Hz, 1H), 2.23 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), −0.06 (s, 3H). LCMS (ESI+νe ion) m/z: [M+H]: 432.2.

2-(((1R,2S)-1-Ethoxy-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole, Example 113.6

To a solution of 2-(((1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole (130 g, 301 mmol, 1.0 equiv) in DCM (1300 mL, 10.00 mL/g) at 0° C. was added 3-chloroperoxybenzoic acid (70-75%) (148 g, 602 mmol, 2.0 equiv) in portions. The reaction mixture was allowed to warm to RT and continued to stir for 3 h. Saturated aqueous NaHCO₃ solution (500 mL) was added and the reaction mixture was stirred for 10 min. The resulting mixture was then extracted with DCM (2×500 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain the initial product which was further purified by silica gel column chromatography (elution: 20-40% EtOAc in hexane) to obtain 2-(((1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole (75 g, 58%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (t, J=0.9 Hz, 2H), 8.21-8.16 (m, 1H), 8.03-7.98 (m, 1H), 7.66-7.56 (m, 2H), 5.73 (d, J=4.7 Hz, 1H), 4.45 (ddd, J=8.8, 5.4, 1.7 Hz, 1H), 2.23 (d, J=1.0 Hz, 3H), 1.56 (dd, J=7.1, 0.9 Hz, 3H), 0.90 (d, J=0.9 Hz, 9H), 0.16 (s, 3H), −0.07 (s, 3H). LCMS (ESI+νe ion) m/z: [M+H]: 464.4.

(1R,2S)-1-((tert-Butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, Example 113.0

To a suspension of 2-(((1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-chloropyrimidin-2-yl)propan-2-yl)sulfonyl)benzo[d]thiazole (62 g, 134 mmol, 1.0 equiv) in MeOH (620 mL, 10 mL/g) was added potassium carbonate (37 g, 267 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred at the same temperature for 3 h. The reaction was then concentrated under reduced pressure to give the initial product which was suspended in water (620 mL, 10 mL/g) and treated with (aminooxy)sulfonic acid (30.2 g, 267 mmol, 2.0 equiv) and potassium acetate (13.12 g, 134 mmol, 1.0 equiv) at 0° C. and then stirred at RT for 16 h. The reaction mixture was extracted with DCM (3×200 mL). The combined organic layers were dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain the initial material which was purified by column chromatography (eluent: 60-80% EtOAc in petroleum ether) to obtain ((1R,2S)-1-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide (40 g, 87%) as a thick brown oil with 80% ee. The enriched material was purified by chiral SFC to achieve an ee % of >95%: Chiralpak AD-H (2×15 cm)+AD-H (2×25 cm)+AD-H (2×15 cm) column, 20% EtOH/CO₂, Flowrate: 70 mL/min to give Example 113.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=0.9 Hz, 2H), 6.77 (s, 2H), 5.26 (d, J=4.8 Hz, 1H), 3.61 (qd, J=6.9, 4.8 Hz, 1H), 2.28 (t, J=0.8 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H), 0.81 (s, 9H), 0.03 (s, 3H), 0.17 (s, 3H). LCMS (ESI+νe ion) m/z: [M+H]: 346.4.

The compounds set forth in the following table were synthesized following the procedure in Example 91.1 using the known starting material as described.

TABLE 23 Example Reagents Structure, Name and Data 116.1 2-methyl-2H-indazole- 4-carboxylic acid methyl ester (commercially available from Synthonix).

LCMS-ESI (pos.) m/z: 191.0 (M + H)⁺.

The compounds set forth in the following table were synthesized following the procedure in Example 96.1 using the known starting material as described.

TABLE 24 Example Reagents Structure, Name and Data 117.1 1-(methoxymethyl)cyclo- butanamine hydrochloride (commercially available from Enamine), Hunig's base (commercially available from Sigma-Aldrich Chemical Company, Inc.).

¹H NMR (400 MHz, CD₃CN) δ 1.73-1.97 (m, 2 H) 2.18-2.26 (m, 2 H) 2.31-2.40 (m, 2 H) 3.40 (s, 3 H) 3.52 (s, 2 H). 119.1 (3S)-oxan-3-amine hydrochloride (commerically available from Accela ChemBio Inc), Hunig's base (commercially available from Sigma-Aldrich Chemical Company, Inc.).

¹H NMR (400 MHz, CDCl₃) δ 3.81-3.85 (m, 1H), 3.55-3.72 (m, 4H), 2.04-2.11 (m, 1H), 1.81- 1.89 (m, 2H), 1.56-1.64 (m, 1H). 118.1 (3R)-oxan-3-amine hydrochloride (commerically available from Accela ChemBio Inc), Hunig's base (commerically available from Sigma-Aldrich Chemical Company, Inc.).

¹H NMR (400 MHz, CDCl₃) δ 3.81-3.85 (m, 1H), 3.55-3.72 (m 4H), 2.04-2.11 (m, 1H), 1.81- 1.89 (m, 2H), 1.56-1.64 (m, 1H). 114.1 1-(methoxymethyl)cyclo- propanamine hydrochloride (commercially available from J&W Pharm Lab), N,N-diisopropylethylamine (commercially available from Sigma Aldrich).

¹H NMR (400 MHz, CDCl₃) δ 3.47 (s, 2H), 3.43 (s, 3H), 1.06- 1.16 (m, 2H), 0.81-0.94 (m, 2H).

The compounds set forth in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 25 Example Reagents Structure, Name and Data 114.0 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-3-carbohydrazide (Example 116.1), 1- isothiocyanato-1- (methoxymethyl)cyclopropane Example 114.1), and (1R,2S)- 1-(5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide (Example 103.3),

¹H NMR (500 MHz, DMSO-d₆) δ 12.94-13.25 (m, 1 H) 8.84-9.04 (m, 2 H) 8.22-8.41 (m, 1 H) 7.99-8.12(m, 1 H) 7.71-7.83 (m, 1 H) 7.24-7.44 (m, 1 H) 4.93-5.12 (m, 1 H) 4.19-4.25 (m, 3 H) 3.44-3.59 (m, 1 H) 3.32-3.35 (m, 3 H) 3.11-3.17 (m, 3 H) 1.30-1.36 (m, 3 H) 0.24-1.12 (m, 6 H). LCMS- ESI (pos.) m/z: 547.2 (M + H)⁺. 115.0 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-3-carbohydrazide (Example 116.1), isothiocyanatocyclopropane (commercially available from Lancaster), and (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide (Example 103.3),

¹H NMR (500 MHz, DMSO-d6) δ 12.90-13.11 (m, 1 H) 8.91-8.99 (m, 2 H) 8.36-8.49 (m, 1 H) 7.75-7.84 (m, 1 H) 7.51-7.66 (m, 1 H) 7.32-7.51 (m, 1 H) 4.89-5.04 (m, 1 H) 4.16-4.23 (m, 3 H) 3.48-3.65 (m, 1 H) 3.17-3.23 (m, 1 H) 3.13-3.16 (m, 3 H) 1.31-1.38 (m, 3 H) 0.80-0.95 (m, 2 H) 0.66-0.74 (m, 1 H) 0.46-0.55 (m, 1 H). LCMS-ESI (pos.) m/z: 50.2 (M + H)⁺. 116.0 2-methyl-2H-indazole-4- carbohydrazide (Example 116.1), 2-isothiocyanatopropane (commercially available from Sigma-Aldrich), and (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide (Example 103.3).

¹H NMR (400 MHz, DMSO-d₆) δ 12.80-13.28 (m, 1 H) 8.81-9.00 (m, 2 H) 8.27-8.44 (m, 1 H) 7.74-7.98 (m, 1 H) 7.30-7.52 (m, 1 H) 7.16-7.30 (m, 1 H) 4.92-5.05 (m, 1 H) 4.05-4.30 (m, 4 H) 3.43-3.68 (m, 1 H) 3.21 (s, 3 H) 1.36-1.46 (m, 6 H) 1.31-1.36 (m, 3 H). LCMS-ESI (pos.) m/z: 505.0 (M + H)⁺. 117.0 2-methyl-2H-indazole-4- carbohydrazide (Example 116.1), 1-isothiocyanato-1- (methoxymethyl)cyclobutane (Example 117.1), and (1R,2S)-1- (5-chloropyrimidin-2-yl)-1- methoxypropane-2-sulfonamide (Example 103.3).

¹H NMR (500 MHz, CDCl₃) δ 8.69-8.85 (m, 2 H) 8.11-8.27 (m, 1 H) 7.97- 8.06 (m, 1 H) 7.81-7.96 (m, 1 H) 7.38-7.51 (m, 1 H) 5.10-5.15 (m, 1 H) 4.30-4.38 (m, 3 H) 4.07 (br s, 2 H) 3.71-3.77 (m, 1 H) 3.47-3.54 (m, 3 H) 3.36-3.43 (m, 3 H) 1.93-2.40 (m, 4 H) 1.62-1.82 (m, 2 H) 1.42-1.49 (m, 3 H). LCMS-ESI (pos.) m/z: 561.2 (M + H)⁺. 118.0 2-methoxybenzhydrazide (commercially available from Alfa Aesar), (R)-3- isothiocyanatotetrahydro-2H- pyran (Example 118.1), and (1R,2S)-1-methoxy-1- (5-chloropyrimidin-2- yl)propane-2-sulfonamide (Example 103.3).

¹H NMR (500 MHz, DMSO-d₆) δ 12.96-13.12 (m, 1 H) 8.88-9.04 (m, 2 H) 7.56-7.71 (m, 1 H) 7.37-7.54 (m, 1 H) 7.20-7.37 (m, 1 H) 7.08-7.20 (m, 1 H) 4.81-5.09 (m, 1 H) 3.91-4.07 (m, 1 H) 3.82-3.88 (m, 3 H) 3.61-3.79 (m, 2 H) 3.57 (tt, J = 11.4, 4.2 Hz, 1 H) 3.50 (qd, J = 6.9, 4.0 Hz, 1 H) 3.10-3.20 (m, 4 H) 2.40-2.48 (m, 1 H) 1.73-1.89 (m, 1 H) 1.64-1.73 (m, 1 H) 1.39-1.55 (m, 1 H) 1.29-1.35 (m, 3 H). LCMS-ESI (pos.) m/z: 523.2 (M + H)⁻. 119.0 3-methoxybenzhydrazide (commercially available from Enamine), (S)-3- isothiocyanatotetrahydro-2H- pyran (Example 119.1), and (1R,2S)-1-methoxy- 1-(5-chloropyrimidin-2- yl)propane-2-sulfonamide (Example 103.3).

¹H NMR (500 MHz, DMSO-d₆) δ 12.95-13.16 (m, 1 H) 8.86-9.04 (m, 2 H) 7.43-7.58 (m, 1 H) 7.02-7.26(m, 3 H) 4.80-5.02 (m, 1 H) 3.98-4.09 (m, 1 H) 3.86-3.95 (m, 2 H) 3.80-3.84 (m, 3 H) 3.71-3.80 (m, 1 H) 3.48-3.58 (m, 1 H) 3.14-3.22 (m, 4 H) 2.52-2.59 (m, 1 H) 1.81-1.90 (m, 1 H) 1.63-1.71 (m, 1 H) 1.41-1.56 (m, 1 H) 1.29-1.36 (m, 3 H). LCMS-ESI (pos.) m/z: 523.2 (M + H)⁺. 120.0 2-methyl-2H-indazole- 4-carbohydrazide (Example 116.1), 4-isothiocyanatotetrahydro- 2H-pyran (commercially available from Oakwood Products, Inc.), and ((2S,3R)-3-(5-methylpyrimidin- 2-yl)butane-2-sulfonamide (Example 102.0).

¹H NMR (400 MHz, CDCl₃) δ 0.93 (d, J = 6.74 Hz, 1 H) 1.25 (t, J = 7.00 Hz, 5 H) 1.42-1.57 (m, 9 H) 1.57-1.84 (m, 3 H) 2.30 (s, 4 H) 2.80 (br dd, J = 12.44. 2.38 Hz, 2 H) 3.28 (br t, J = 12.13 Hz, 2 H) 3.73 (q, J = 7.05 Hz, 3 H) 3.81-3.90 (m, 1 H) 3.92-4.14 (m, 4 H) 4.27 (s, 4 H) 7.14 (d, J = 6.84 Hz, 1 H) 7.41 (dd, J = 8.71, 6.95 Hz, 1 H) 7.92 (d, J = 8.81 Hz, 1 H) 8.05 (s, 1 H) 8.51-8.56 (m, 2 H). LCMS-ESI (pos.) m/z: 511.2 (M + H)⁺.

Example 121.0. Preparation of: (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-cyclopropyl-5-(3-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide

3-(Methylsulfonyl)benzohydrazide hydrochloride, Example 121.1

A solution of tert-butyl carbazate (commercially available from Aldrich, 0.604 g, 4.57 mmol), 3-methanesulfonylbenzoyl chloride (commercially available from Adlab Chemicals, 1.00 ml, 4.57 mmol), and N,N-diisopropylethylamine (0.8 ml, 4.57 mmol) in THF (10 mL) was stirred at room temperature for one hour. The reaction mixture was diluted with DCM and washed with citric acid solution (1M aqueous). The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was treated with HCl (4M in dioxane (5.72 ml, 22.9 mmol)) and was allowed to stir overnight at room temperature. The reaction mixture was then concentrated yielding 3-(methylsulfonyl)benzohydrazide (0.750 g, 3.50 mmol, 77% yield) as the HCl salt. LCMS (pos.) m/z: 215.0 (M+H)⁺.

(1R,2S)-1-(5-Chloropyrimidin-2-yl)-N-((E)-N-cyclopropyl-N′-(3-(methylsulfonyl)benzoyl)carbamohydrazonoyl)-1-methoxypropane-2-sulfonamide, Example 121.2

A solution of (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide ((Example 103.3, 0.268 g, 1.01 mmol), isothiocyanatocyclopropane (commercially available from Alpha Aesar, 0.100 g, 1.01 mmol), and cesium carbonate (0.329 g, 1.01 mmol) in ACN (5 mL) was stirred at room temperature for one hour. Next, 3-(methylsulfonyl)benzohydrazide hydochloride (0.238 g, 1.11 mmol) was added followed by silver nitrate (0.343 g, 2.02 mmol). After stirring for an additional hour, the reaction mixture was purified directly by silica gel column chromatography (0-97% EtOAc/heptane, 3% MeOH) yielding 121.2 (0.340 g, 0.62 mmol, 62% yield). LCMS (pos.) m/z: 545.0 (M+H)⁺.

(1R,2S)-1-(5-Chloropyrimidin-2-yl)-N-(4-cyclopropyl-5-(3-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide, Example 121.0

A solution of (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-((E)-N-cyclopropyl-N′-(3-(methylsulfonyl)benzoyl)carbamohydrazonoyl)-1-methoxypropane-2-sulfonamide (0.340 g, 0.624 mmol) in 3 mL IPA was treated with sodium hydroxide 1.0M (0.811 ml, 0.811 mmol) and the mixture was heated at reflux for 4 hours. The reaction mixture was then poured into saturated aqueous NH₄Cl solution and was extracted with DCM. The organic layers were combined and dried over MgSO₄ and concentrated. Purification of the residue by silica gel column chromatography (0-100% EtOAc/heptane) gave (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-cyclopropyl-5-(3-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide (0.076 g, 0.144 mmol, 23% yield) as a white solid. ¹H NMR (500 MHz, CD₃CN) δ 0.58-0.69 (m, 1H) 0.74-0.82 (m, 1H) 0.92-1.03 (m, 2H) 1.38 (d, J=7.14 Hz, 1H) 3.12 (s, 1H) 3.20 (s, 1H) 3.53-3.62 (m, 1H) 4.96 (d, J=4.41 Hz, 1H) 7.80 (s, 1H) 8.05-8.13 (m, 2H) 8.27 (s, 1H) 8.78 (s, 2H) 11.19 (br s, 1H). LCMS (pos.) m/z: 527.0 (M+H)⁺.

Example 122.0. Preparation of (1R,2S)-1-(5-chloropyrimidin-2-yl)-N-(4-cyclopropyl-5-(3-(difluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide

3-(Difluoromethoxy)benzohydrazide hydrochloride, Example 122.1

A solution of 3-(difluoromethoxy)benzoic acid (commercially available from Alpha Aesar, 2.00 g, 10.63 mmol) in ACN (11 mL) was treated with thionyl chloride (2.33 mL, 31.9 mmol), and the mixture was then heated at reflux for one hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (10 mL) and treated with tert-butyl carbazate (commercially available from Aldrich, 1.405 g, 10.63 mmol) followed by N,N-diisopropylethylamine (1.86 mL, 10.63 mmol). After stirring for 20 min., the reaction mixture was purified directly by silica gel column chromatography (0-100% EtOAc/heptane). The product fractions were concentrated and treated with HCl (4M in dioxane, 13.29 ml, 53.2 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated yielding 3-(difluoromethoxy)benzohydrazide hydrochloride (1.24 g, 5.18 mmol, 49% yield). LCMS (pos.) m/z: 203.2 (M+H)⁺.

(1R,2S)-1-(5-Chloropyrimidin-2-yl)-N-((E)-N-cyclopropyl-N′-(3-(difluoromethoxy)benzoyl)carbamohydrazonoyl)-1-methoxypropane-2-sulfonamide, Example 122.2

A solution of (1R,2S)-1-(5-chloropyrimidin-2-yl)-1-methoxypropane-2-sulfonamide (Example 103.3, 0.268 g, 1.01 mmol), isothiocyanatocyclopropane (commercially available from Aldrich, 0.100 g, 1.01 mmol), and cesium carbonate (0.986 g, 3.03 mmol) in 5 mL ACN was stirred at room temperature for one hour. Example 122.1 (0.224 g, 1.109 mmol) was then added followed by silver nitrate (0.343 g, 2.02 mmol). After stirring for 1 h, the reaction mixture was purified directly by silica gel column chromatography (0-97% EtOAc/heptane, 3% MeOH) yielding 122.2 (0.290 g, 0.544 mmol, 54% yield). LCMS (pos.) m/z: 533.2 (M+H)⁺.

(1R,2S)-1-(5-Chloropyrimidin-2-yl)-N-(4-cyclopropyl-5-(3-(difluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)-1-methoxypropane-2-sulfonamide, Example 122.0

A solution of Example 122.2 (0.290 g, 0.544 mmol) in IPA (3 mL) was treated with sodium hydroxide (1.0 M, 0.707 ml, 0.707 mmol) and was heated to reflux for 4 h. The reaction mixture was poured into saturated aqueous NH₄Cl solution and extracted with DCM. The organic layers were combined and dried over MgSO₄ and concentrated in vacuo. purification of the residue by silica gel column chromatography (0-100% EtOAc/heptane) gave 122.0 (0.023 g, 0.045 mmol, 8% yield) as a white solid. ¹H NMR (500 MHz, CD₃CN) 60.58-0.81 (m, 2H) 0.86-1.02 (m, 3H) 1.15-1.24 (m, 1H) 1.37 (d, J=7.01 Hz, 1H) 3.05 (s, 1H) 3.19 (s, 1H) 3.56 (dd, J=7.01, 4.41 Hz, 1H) 4.95 (d, J=4.41 Hz, 1H) 6.67-7.00 (m, 1H) 7.37 (s, 1H) 7.51 (s, 1H) 7.55-7.66 (m, 1H) 8.77 (s, 2H) 11.13 (br s, 1H). LCMS (pos.) m/z: 515.1 (M+H)⁺.

The compounds in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 26 Example Reagents Structure, Name and Data 123.0 (1S,2S)-1-(5- chloropyrimidin-2-yl)-1- isopropoxypropane-2- sulfonamide (Example 104.1), benzhydrazide (commercially available from Acros Organics), and 2-isothiocyanato- 1,3-dimethoxypropane (Example 96.1).

¹H NMR (400 MHz, CDCl₃) δ 12.03 (br s, 1 H) 8.75 (s, 2 H) 7.68 (dd, J = 7.93, 1.61 Hz, 2 H) 7.46-7.59 (m, 3 H) 4.92 (d, J = 3.84 Hz, 1 H) 4.48 (tt, J = 9.02, 4.66 Hz, 1 H) 4.28 (t, J = 9.59 Hz, 1 H) 4.17 (t, J = 9.33 Hz, 1 H) 3.84 (qd, J = 7.01, 3.84 Hz, 1 H) 3.54-3.65 (m, 3 H) 3.33 (s, 3 H) 3.27 (s, 3 H) 1.59 (d, J = 7.05 Hz, 3 H) 1.13 (d, J = 6.01 Hz, 3 H) 0.99 (d, J = 6.12 Hz, 3 H). Mass Spectrum (pos.) m/z: 539.2 (M + H)⁺. 124.0 (1R,2S)-1-(5- chloropyrimidin-2-yl)- 1-methoxypropane-2- sulfonamide (Example 103.3), benzhydrazide (commercially available from Acros Organics), and (R)-2-isothiocyanato- 1-methoxypropane (Example 124.1).

¹H NMR (500 MHz, CDCl₃) δ 11.25 (br s, 1 H) 8.70 (s, 2 H) 7.56-7.61 (m, 2 H) 7.44-7.55 (m, 3 H) 5.08 (d, J = 4.28 Hz, 1 H) 4.34-4.45 (m, 1 H) 4.22 (t, J = 9.80 Hz, 1 H) 3.72 (qd, J = 7.01,4.28 Hz, 1 H) 3.42 (dd, J = 9.86, 4.54 Hz, 1 H) 3.36 (s, 3 H) 3.28 (s, 3 H) 1.47 (d, J = 7.14 Hz, 3 H) 1.43 (d, J = 7.01 Hz, 3 H). Mass Spectrum (pos.) m/z: 481.0 (M + H)⁺. 125.0 (1S,2S)-1-isopropoxy-1- (5-methylpyrimidin-2- yl)propane-2-sulfonamide (Example 104.1), benzhydrazide (commercially available from Acros Organics), and isothiocyanatocyclopropane (commercially available from Sigma Aldrich).

¹H NMR (600 MHz, DMSO-d₆) δ 12.75 (s, 1 H) 8.97 (s, 2 H) 7.77 (dd, J = 7.86, 1.64 Hz, 2 H) 7.51-7.61 (m, 3 H) 4.89 (d, J = 7.40 Hz, 1 H) 3.59 (quin, J = 7.18 Hz, 1 H) 3.22 (tt, J = 7.06, 3.68 Hz, 1 H) 1.18 (d, J = 6.15 Hz, 1 H) 1.09 (d, J = 7.08 Hz, 3 H) 1.00 (d, J = 6.07 Hz, 3 H) 0.92-0.99 (m, 1 H) 0.79-0.91 (m, 2 H) 0.67 (d, J = 6.15 Hz, 3 H) 0.38- 0.46 (m, 1 H). Mass Spectrum (pos.) m/z: 477.0 (M + H)⁺. 126.0 (2S,3R)-3-(5- chloropyrimidin-2- yl)butane-2-sulfonamide (Example 102.4), benzhydrazide (commercially available from Acros Organics), and (S)-2-isothiocyanato- 1-methoxypropane (Example 126.1).

¹H NMR (600 MHz, DMSO-d₆) δ 13.02 (s, 1 H) 8.88 (s, 2 H) 7.59 (s, 5 H) 4.21-4.32 (m, 1 H) 4.03 (br t, J = 9.89 Hz, 1 H) 3.73-3.81 (m, 1 H) 3.64-3.73 (m, 1 H) 3.36-3.38 (m, 1 H) 3.11 (s, 3 H) 1.39 (d, J = 7.01 Hz, 3 H) 1.36 (d, J = 7.08 Hz, 3 H) 1.27 (d, J = 7.01 Hz, 3 H). Mass Spectrum (pos.) m/z: 465.0 (M + H)⁺. 127.0 2S,3R)-3-(5-chloropyridin- 2-yl)butane-2-sulfonamide (Example 127.1), benzhydrazide (commercially available from Acros Organics), and 5-isothiocyanato-4,6- dimethoxypyrimidine (Example 1.1).

¹H NMR (500 MHz, DMSO-d₆) δ 13.48 (s, 1 H) 8.67 (s, 1 H) 8.55 (d, J = 2.49 Hz, 1 H) 7.87 (dd, J = 8.41, 2.57 Hz, 1 H) 7.49-7.55 (m, 1 H) 7.45 (t, J = 7.67 Hz, 2 H) 7.35-7.40 (m, 2 H) 7.31 (d, J = 8.49 Hz, 1 H) 3.87 (s, 3 H) 3.87 (s, 3 H) 3.59 (qd, J = 7.03, 3.43 Hz, 1 H) 3.41 (qd, J = 6.90. 3.50 Hz, 1 H) 1.22 (d, J = 7.08 Hz, 3 H) 1.09 (d, J = 7.01 Hz, 3 H). Mass Spectrum (pos.) m/z: 530.0 (M + H)⁺. 128.0 (2S,3R)-3-(5- methoxypyrimidin-2- yl)butane-2-sulfonamide (Example 108.1), 2- bromobenzohydrazide (commercially available from CombiBlock), and 5-isothiocyanato-2,2- dimethyl-1,3-dioxane (Example 128.1).

¹H NMR (500 MHz, CDCl₃) δ 11.48 (s, 1 H) 8.39 (s, 2 H) 7.74-7.81 (m, 1 H) 7.49-7.55 (m, 2 H) 7.39-7.47 (m, 1 H) 4.60-5.24 (m, 2 H) 3.36-4.26 (m, 8 H) 1.60 (s, 3 H) 1.52 (d, J = 7.01 Hz, 3 H) 1.49 (d, J = 7.14 Hz, 3 H) 1.36 (s, 3 H). Mass Spectrum (pos.) m/z: 581.0, 583.0 (M + H)⁺.

Example 124.1. Preparation of (R)-2-isothiocyanato-1-methoxypropane

(R)-2-Isothiocyanato-1-methoxypropane, Example 124.1

Example 124.1 was prepared from (2R)-1-methoxy-2-propanamine (commercially available from Sigma Aldrich) using the procedure described in Example 96.1. ¹H NMR (400 MHz, CD₃CN) δ 4.03 (m, 1H) 3.39-3.50 (m, 2H) 3.37 (s, 3H) 1.30 (d, J=6.74 Hz, 3H).

Example 126.1. Preparation of (S)-2-isothiocyanato-1-methoxypropane

(S)-2-Isothiocyanato-1-methoxypropane, Example 126.1

Example 126.1 was prepared from (2S)-1-methoxy-2-propanamine (commercially available from Sigma Aldrich) using the procedure described in Example 96.1. ¹H NMR (400 MHz, CDCl₃) δ 3.93 (m, 1H) 3.36-3.46 (m, 5H) 1.33 (d, J=6.74 Hz, 3H).

Example 127.1. Preparation of (2S,3R)-3-(5-chloropyridin-2-yl)butane-2-sulfonamide

(2S,3R)-3-(5-Chloropyridin-2-yl)butane-2-sulfonamide, Example 127.1. Example 127.1 was prepared from 2-bromo-5-chloropyridine (commercially available from Sigma Aldrich) using the procedure as described in Example 102.0. ¹H NMR (400 MHz, DMSO-d₆) δ 1.19 (d, J=7.05 Hz, 3H) 1.29 (d, J=7.05 Hz, 3H) 3.46 (qd, J=7.08, 3.84 Hz, 1H) 3.63 (qd, J=7.08, 3.84 Hz, 1H) 6.82 (s, 2H) 7.36 (d, J=8.50 Hz, 1H) 7.88 (dd, J=8.50, 2.70 Hz, 1H) 8.56 (d, J=2.28 Hz, 1H). LCMS-ESI (pos.) m/z: 249.0 (M+H)⁺.

Example 128.1. Preparation of 5-isothiocyanato-2,2-dimethyl-1,3-dioxane

5-Isothiocyanato-2,2-dimethyl-1,3-dioxane, Example 128.1

Example 128.1 was prepared from 2,2-dimethyl-1,3-dioxan-5-amine (commercially available from ChemBridge) using the procedure as described in Example 96.1. ¹H NMR (400 MHz, CDCl₃) δ 4.08 (dd, J=12.02, 3.42 Hz, 2H) 3.87 (dd, J=12.13, 5.08 Hz, 2H) 3.55 (tt, J=5.07, 3.43 Hz, 1H) 1.47 (s, 3H) 1.43 (s, 3H).

The compounds in the following table were synthesized following the procedure in Example 21.0 using the known starting material as described.

TABLE 27 Example Reagents Structure, Name and Data 129.0 (1R,2S)-1-(5- chloropyrimidin-2-yl)-1- methoxypropane-2- sulfonamide (Example 103.3), benzhydrazide (commercially available from Acros Organics), and 2-methoxyethyl isothiocyanate (commercially available from Sigma Aldrich).

¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (br s, 1H), 8.94 (s, 2H), 7.72 (d, J = 7.0 Hz, 2H), 7.63-7.52 (m, 3H), 4.92 (d, J = 4.1 Hz, 1H), 3.94- 3.82 (m, 2H), 3.63-3.49 (m, 3H), 3.15 (s, 3H), 3.12-3.06 (m, 3H), 1.31 (d, J = 6.8 Hz, 3H). LCMS-ESI (pos.) m/z: 467.0 (M + H)⁺.

Biological Activity

[³⁵S]GTPγS Binding

The human APJ receptor was cloned by polymerase chain reaction and the gene encoding the receptor was subcloned in pFLAG-CMV™-3 expression vector (Sigma, Saint Louis, Mo. USA) in-house at Amgen. A GTPγS binding assay was performed on membranes prepared from CHO cells stably expressing human APJ receptor. The optimum experimental conditions for the concentrations of GDP, MgCl₂, and NaCl in the assay buffer were initially determined. The assay was performed in 9 μL assay buffer [20 mM HEPES, pH 7.5, 5 mM MgCl₂, 100 mM NaCl and 0.1% (w/v) BSA], 1 μL of diluted test compound (starting with 0.75 mM, 2-fold serial dilution with DMSO, total 22 points), 10 μL of 18 μM GDP (final concentration of 3 μM GDP), 20 μL of 0.25 μg/mL membrane protein expressing human APJ receptor captured with WGA PS beads (final concentration of 5 μg per well), and 20 μL of 0.3 nM [³⁵S]GTPγS (final concentration is 0.1 nM [³⁵S]GTPγS)(Perkin Elmer Life and Analytical Sciences, Waltham USA). One column of the plate was 1 μL of DMSO as background and another column of the plate was 1 μL of 180 μM Pyr-Apelin-13 which was used as control at a final concentration of 3 μM. Incubation was at RT for 90 min and the microplate was read using a ViewLux™ ultra HTS Microplate Imager (PerkinElmer, Inc.). All the results presented are means of several independent experiments and analyzed by non-linear regression methods using the commercially available program Prism (GraphPad, San Diego, Calif.) providing the EC₅₀ values detailed in Table 28.

Evidence for Load Independent Inotropic Effects with APJ Agonists Using Ex Vivo Assay (Isolated Perfused Rat Hearts)

Naive Sprague Dawley® SD rats (Harlan laboratories (Livermore, Calif. USA)) were anaesthetized and hearts were excised followed by cannulation in the Langendorff apparatus (Harvard apparatus, Holliston, Mass. USA) via aorta. The heart was perfused retrograde with modified oxygenated Krebs-Henseleit buffer (Skrzypiec-Spring M et al., (2007) J. Pharmacol Toxicol Methods 55: 113-126). The pressure of the solution causes the aortic valve to shut and the perfusate is then forced into the ostium and the coronary vessels. This allows the heart to beat for several h. A balloon was inserted into the left ventricle (LV) to measure dP/dt_(max) (derivative of left ventricular pressure) as an index of cardiac contractility. The APJ agonist was perfused constantly in a dose dependent manner into the heart to examine cardiac contractility. Administration of APJ agonist showed a dose-dependent increase in inotropic and lusitropic effects (Table 29). APJ agonists of the present invention showed improvement in cardiac contractility and relaxation when perfused into the heart as described above.

Evidence for Improvement in Cardiac Contractility In Vivo in Heart Failure Rat Model

Based on the ex vivo findings in isolated heart assay, APJ agonists were dosed in vivo to investigate the translation of cardiac contractility in in vivo settings. Male Lewis rats (Charles River, USA) at 2-3 months of age were used for the study. Heart failure was induced by permanent ligation of the left descending coronary artery which results in injury to the heart with an ejection fraction of <35%. APJ agonists were administered dose dependently acutely for a period of 30 min. Administration of example compounds lead to an increase in cardiac contractility as measured by dP/dt_(max) (derivative of left ventricular pressure) (Table 29).

The following table includes biological activity data obtained using the procedures and assays set forth above for the Example compounds described herein.

TABLE 28 Biological Activity Information for Example Compounds. Example(s) Activity hAPJ SPA EC₅₀ IP (μM) 1.0 0.0042 2.0 0.11 3.0 0.0053 4.0 0.0029 5.0 0.0023 6.0 0.0068 7.0 0.0014 8.0 0.015 9.0 0.040 10.0 0.042 11.0 0.0064 12.0 0.0085 13.0 0.00022 14.0 0.00055 15.0 0.00089 16.0 0.00020 17.0 0.00089 18.0 0.00081 19.0 0.040 20.0 0.0053 21.0 0.0073 22.0 0.17 23.0 0.0059 24.0 0.00027 25.0 0.0013 26.0 0.0052 27.0 0.032 28.0 0.41 29.0 0.39 30.0 0.10 31.0 0.34 32.0 0.017 33.0 0.23 34.0 0.028 35.0 0.28 36.0 0.0019 37.0 — 38.0 — 39.0 0.16 40.0 0.0044 41.0 0.0047 42.0 0.0034 43.0 0.016 44.0 0.15 45.0 0.034 46.0 0.0017 47.0 0.048 48.0 0.023 49.0 0.094 50.0 0.11 51.0 — 52.0 0.0033 53.0 0.0049 54.0 0.014 55.0 0.00033 56.0 0.030 57.0 0.0014 58.0 0.00094 59.0 0.086 60.0 0.35 61.0 0.069 62.0 0.074 63.0 0.42 64.0 0.0047 65.0 0.23 66.0 0.00073 67.0 0.0059 68.0 0.0047 69.0 0.035 70.0 0.0038 71.0 0.16 72.0 0.0045 73.0 0.031 74.0 0.14 75.0 0.013 76.0 0.00051 77.0 0.0010 78.0 0.0024 79.0 0.0038 80.0 0.0035 81.0 0.00027 82.0 >4.2 83.0 0.089 84.0 0.055 85.0 0.00092 86.0 0.0106 87.0 0.00056 88.0 0.023 89.0 0.00047 90.0 0.54 91.0 0.0020 92.0 0.060 93.0 0.041 94.0 0.0029 95.0 0.34 96.0 0.016 97.0 0.0010 98.0 0.0033 99.0 0.0080 110.0 0.075 114.0 0.053 115.0 0.011 116.0 0.22 117.0 0.34 118.0 0.18 119.0 0.022 120.0 0.59 121.0 0.59 122.0 0.25 123.0 0.0072 124.0 0.057 125.0 — 126.0 0.017 127.0 0.00096 128.0 0.91 129.0 0.014

The following table includes data obtained using the procedures and assays set forth above for the Example compounds described herein.

TABLE 29 Contractile Effects of Examples Observed in ex vivo (Isolated Heart Assay) and in vivo (MI Rat Model). Isolated Heart Assay MI Rat Model Example(s) dP/dt_(max) (%) dP/dt_(min) (%) dP/dt_(max) (%) 4 6.96 3.22 20 17 8.71 16.1 nd* 20 1.26 1.10 nd* 24 12.5 18.5 nd* 42 No effect No effect nd* *nd is not determined

APJ is a G-protein coupled receptor that is closely related to the Angiotensin II Type 1 receptor (AT1R) with 50% homology in the transmembrane domain. Apelin is a known endogenous ligand for APJ and recently another ligand named ELABELA has been identified as another potential ligand for the APJ receptor (Tatemoto, K. et al., Biochem. Biophys. Res. Commun., 251, pp. 471-476 (1998); Pauli, A. et al., Science, 343, pp. 1248636 (2014)). Since its discovery, there is accumulating evidence indicating the role of the apelin-APJ receptor in the pathophysiology of cardiovascular diseases. Pre-clinical and clinical studies have shown that acute infusion of apelin or APJ agonists improve cardiac function under heart failure settings (Berry, M. F., et al., Circulation, 110(11) pp. 11187-11193 (2004); Japp, A. G. et al., Circulation, 121, pp. 1818-1827 (2010)).

A key emerging aspect of the apelin-APJ system is its interaction with the renin-angiotensin system. Apelin is also known to counter-regulate the vasoconstriction actions of AngII. Apelin knockout mice show a strong increased vasopressor response to AngII indicating that the apelin/APJ system exerts the hypotensive effect in vivo against the pressor action of AngII. In addition, the apelin activated APJ pathway inhibited angiotensin-mediated formation of atherosclerosis through interaction with the AT1R (Chun, H. J., et al., J. Clin. Invest., 118, pp. 3343-3354 (2008), Siddiquee, K. et al., J. Hypertens., 29, pp. 724-731 (2011), Sun, X. et al., Hypertens. Res., 34, pp. 701-706 (2011)). This could be mediated by convergence of two independent intracellular signaling pathways or via direct physical interaction of APJ with AT1R to form a heterodimer. Siddiquee et al. showed that the AngII signaling is antagonized through apelin-dependent heterodimerization and APJ mediated negative allosteric modulation of AT1R function (Siddiquee, K. et al., Br. J. Pharmacol., 168, pp. 1104-1117 (2013).

We were interested to understand if the heterodimerization of APJ-AT1R upon activation by APJ agonists would have any beneficial outcome clinically in heart failure patients considering most of these patients are on standard of care drugs such as angiotensin blockers (angiotensin II receptor antagonists or angiotensin receptor blockers (ARBs)) and angiotensin converting enzyme (ACE) inhibitors. In order to explore the cross-talk between APJ and the AT1R receptor, we examined IP1 signaling mediated by AT1R upon activation with APJ agonists. Surprisingly and contrary to the findings by Siddique et al., activation of the APJ pathway resulted in positive cooperativity of AngII by shifting its potency to the left and also increasing the efficacy of the IP response (see methods and results section below). Conversely, blocking the AT1R receptor by an ARB such as losartan relieved the inhibition of the APJ receptor and up regulates its signaling which is observed as synergistic effects in both ex-vivo and in vivo studies. This work establishes a new paradigm for cross-talk interaction/heterodimerization between APJ & AT1R which might have implications for approaches to pharmacological interventions in heart failure populations.

The interaction between acetyl cholinesterase (ACE2) and Apelin biology is complicated. To investigate the interaction between the Apelin-APJ and ACE signalling pathways, we examined the improvement in cardiac function with APJ small molecule agonists in the presence of ACE inhibitor captopril in heart failure rats in vivo. Captopril alone, under acute settings, does not show a marked improvement in contractility or ejection fraction acutely. However, in the presence of an APJ agonist, there was a shift in potency to the left with marked improvement in contractility and ejection fraction without changes in heart rate. These findings provide a new reference for the understanding of the regulation of ACE2 for the renin angiotensin aldosterone system (RAAS), independent of AT1R signaling and offer new potential drug targets for the treatment of diseases such as hypertension and heart failure. This work clearly establishes that combination of an agonist of the APJ receptor with an ARB such as losartan and/or with an ACE inhibitor such as captopril which may play an important role in providing greater efficacy in treating heart failure patients, for example in improving contractility and ejection fraction without changing the heart rate.

Evidence for Allosteric Interaction Between APJ and AT1R Using IP Assay

Methods

Single and double stable recombinant cell lines were generated for human APJ and the AT1R receptor in CHO K1 cells tagged either with FLAG or hemagglutinin (HA) tag. Briefly, the CHO-K1 APJ/AT1R cells were seeded in culture medium of DMEM-F12 and 10% FBS at a density of 15 k/well in a 96 well plate overnight. The next day, the culture medium was replaced with medium containing no serum for 4 hours. The compound AngII at a range of concentrations (1 pM-10 μM) with or without different concentrations of APJ agonists were diluted in stimulation buffer and added to the cell plate. The plate was sealed and incubated for 1 hour. This was followed by addition of IP-d2 conjugate followed by europium cryptate antibody conjugate into the wells. The plate was sealed, followed with incubation for 2 hours at RT. Time-resolved fluorescence resonance energy (TR-FRET) at 620 nm and 665 nm was measured after 2 hours with an Envision reader. The signal ratios and delta F were calculated and the amount of IP1 produced was inversely proportional to the TR-FRET ratio, 665/620 nm.

Results

In cells expressing both APJ and the AT1R receptor, addition of APJ agonists at different concentrations increased the maximal response of AngII and also shifted the potency to the left. The increase in IP1 response reached a maximal effect both in potency and Emax indicating a ceiling effect which is a hallmark for allosteric cooperativity between the AT1R and APJ receptor (FIG. 1). However, this effect of cooperativity was not observed in either APJ or AT1R recombinant stable cell lines indicating that there is functional cross-talk between the two receptors through physical interaction or with downstream effectors (FIG. 2 and FIG. 3). Based on the above findings of cooperativity, we rationalized that if an APJ agonist can induce heterodimerization of APJ with AT1R, blocking the AT1R with losartan would enhance the activation of APJ upon addition of small molecule agonists. We observed that APJ small molecule agonists induced positive cooperativity in the presence of AngII and addition of losartan relieved this cooperativity and resulted in synergistic effects of enhancing the efficacy of the APJ receptor. This work clearly establishes that combination of an agonist of the APJ receptor with an ARB such as losartan or an ACE inhibitor such as captopril may play an important role in providing greater efficacy in treatment of heart failure patients.

All publications and patent applications cited in this specification are hereby incorporated by reference herein in their entireties and for all purposes as if each individual publication or patent application were specifically and individually indicated as being incorporated by reference and as if each reference was fully set forth in its entirety. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. 

What is claimed is:
 1. A compound of Formula I or Formula II

or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R¹ is a phenyl group that is unsubstituted or is substituted with 1, 2, or 3 R^(1a) substituents; R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ haloalkyl)-OH, —(C₁-C₆ perhaloalkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents; and further wherein two R^(1a) substituents on adjacent carbon atoms of the phenyl R¹ group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic and may include 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S and may further optionally be substituted with 1 or 2 R^(1a′) substituent and may include an oxo substituent if the ring is not an aromatic ring; R^(1a′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, C₃-C₅ cycloalkyl —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂ or —S(═O)₂—(C₁-C₆ alkyl); R^(1b′) is in each instance independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or —S(═O)₂—(C₁-C₆ alkyl); R² is selected from —H, or C₁-C₄ alkyl or is absent in the compounds of Formula II; R³ is a group of formula —(CR^(3d)R^(3c))—(CR^(3f)R^(3g))-Q; R^(3d) and R^(3e) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl)-phenyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—Si(C₁-C₆ alkyl)₃, —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; R^(3f) and R^(3g) are independently selected from —H, —F, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —O—(C₂-C₆ alkenyl), —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), or —N(C₁-C₆ alkyl)₂; Q is a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C₃-C₈ cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the C₆-C₁₀ aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R^(Q) substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; R^(Q) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NHC(═O)(C₁-C₆ alkyl), —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), phenyl, a heterocyclyl group, a —(C₁-C₆ alkyl)heterocyclyl group, or a heteroaryl group with 5 or 6 ring members and 1, 2, or 3, heteroatoms independently selected from N, O, or S, wherein the heterocyclyl groups of the R^(Q) heterocyclyl and —(C₁-C₆ alkyl)heterocyclyl groups have 3 to 6 ring members of which 1 or 2 are heteroatoms independently selected from N, O, or S, and further wherein the heterocyclyl and the heterocyclyl of the —(C₁-C₆ alkyl)heterocyclyl R^(Q) groups may be further substituted with 1 or 2 oxo substituents and a substituent selected from —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₆ alkyl, or —C(═O)—(C₁-C₆ alkyl); R⁴ is selected from a monocyclic or bicyclic C₆-C₁₀ aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, a monocyclic 3-6 membered cycloalkyl group, or a straight or branched chain C₁-C₆ alkyl group, wherein the C₆-C₁₀ aryl, the heteroaryl, the heterocyclyl, and the cycloalkyl R⁴ group are unsubstituted or are substituted with 1, 2, 3, or 4 R^(4a) substituents, and further wherein the straight or branched chain C₁-C₆ alkyl R⁴ group is unsubstituted or is substituted with 1, 2, or 3 R^(4b) substituents; R^(4a) in each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-OH, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, phenyl, —S(═O)₂—(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-heterocyclyl, or heterocyclyl wherein the heterocyclyl of the —(C₁-C₆ alkyl)-heterocyclyl and heterocyclyl R^(4a) groups is a 3-6 membered ring comprising 1 or 2 heteroatoms independently selected from N, O, or S, and is unsaturated or partially unsaturated and is optionally substituted with 1 or 2 oxo substituents and may include an S═O or SO₂ moiety, and further wherein the heterocyclyl of the R⁴ group may be further substituted with 1 oxo substituent; and R^(4b) in each instance is selected from —F, —Cl, —Br, —I, —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NH(C₁-C₆ alkyl-OH), —N(C₁-C₆ alkyl-OH)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, or, —S(═O)₂—(C₁-C₆ alkyl).
 2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[d]thiazolyl, 2H-indazolyl, quinoxalinyl, quinolinyl, or isoquinolinyl, any of which may unsubstituted or substituted with 1, 2, or 3 independently selected R^(1a′) substituents.
 3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is an unsubstituted phenyl or is a phenyl substituted with 1 or 2 R^(1a) substituents, wherein R^(1a) in each instance is independently selected from —F, —Cl, —Br, —I, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —CN, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), —C₂-C₆ alkenyl, —O—(C₁-C₆ alkyl)-OH, —O—(C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl)-OH, —O—(C₁-C₆ haloalkyl)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ perhaloalkyl)-OH, —O—(C₁-C₆ perhaloalkyl)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —C(═O)—(C₁-C₆ alkyl), —C(═O)OH, —C(═O)—O—(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₆ alkyl), —C(═O)N(C₁-C₆ alkyl)₂, S(═O)₂—(C₁-C₆ alkyl), —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₆ alkyl), —S(═O)₂N(C₁-C₆ alkyl)₂, or —O-phenyl, wherein the phenyl of the —O-phenyl R^(1a) group may optionally be substituted with 1 or 2 R^(1b′) substituents.
 5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R¹ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R² is —H or is absent in the compounds of Formula II.
 7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is a phenyl, pyridinyl, or pyrimidinyl, any of which may be unsubstituted or substituted with 1, 2, 3, or 4 R^(4a) substituents.
 8. The compound of claim 7 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(4a) is in each instance independently selected from —F, —Br, —Cl, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —OH, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), or —O—(C₁-C₆ perhaloalkyl.
 9. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R⁴ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 10. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyrazine-1-oxide, pyradizinyl, pyridinyl, phenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, piperidin-2-onyl, tetrahydropyrimidin-2(1H)-onyl, 1,3-oxazinan-2-onyl, pyrrolidin-2-onyl, pyrrolidinyl, cyclopentyl, cyclohexyl, benzimidazolyl, isoindolinonyl, 1H-imidazo[4,5-c]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, or 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, any of which may be unsubstituted or substituted with 1 or 2 R^(Q) substituents.
 11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from pyrimidinyl, pyrazinyl, pyridinyl, or phenyl any of which may be unsubstituted or substituted with 1 or 2 R^(Q) substituents.
 12. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R^(Q) in each instance is independently selected from —F, —Cl, —Br, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ perhaloalkyl, —O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆ perhaloalkyl), or —S(═O)—(C₁-C₆ alkyl.
 13. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein Q is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein, R^(3d) and R^(3e) are independently selected from —H, or —C₁-C₆ alkyl; and R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH, or —O—(C₁-C₆ alkyl).
 15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 16. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein R³ is selected from

wherein the symbol

, when drawn across a bond, indicates the point of attachment to the rest of the molecule.
 17. The compound of claim 1, wherein the compound has the formula IA

or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, wherein: R¹ is as defined in claim 1; X is selected from CH or N; Z is selected from CH or N; R^(3d) and R^(3e) are independently selected from —H or —C₁-C₃ alkyl; R^(3f) and R^(3g) are independently selected from —H, —C₁-C₆ alkyl, —OH, or —O—(C₁-C₆ alkyl); Q is a phenyl group or a monocyclic heteroaryl group with 6 ring members containing 1 or 2 N heteroatoms, wherein the phenyl and the monocyclic heteroaryl Q groups are unsubstituted or are substituted with 1 or 2 R^(Q) substituent; and R^(Q) is independently selected from —F, —Cl, —Br, —CN, or —C₁-C₆ alkyl.
 18. A pharmaceutical composition, comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof, and at least one pharmaceutically acceptable excipient.
 19. A pharmaceutical composition, comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
 20. The pharmaceutical composition of claim 18, further comprising a therapeutic agent selected from an α-blocker, a β-blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor. 